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Anaplastic Thyroid Cancer: A Comprehensive Review







  1. Inactivating or Loss-of-function mutations
  2. Activating/Gain-of-Function Mutations
  3. Amplification and Copy Number Gain
  4. Chromosomal Rearrangements
  5. Epigenetic Alterations
  6. MicroRNA Aberrations


  1. p53 Pathway
  2. RAS/RAF/MAPK Pathway
  3. PI3K/AKT/mTOR Pathway
  4. WNT/βCATENIN Pathway
  5. EMT-MET Transition
  6. NF-κB Signaling
  7. Notch Signaling
  8. Cross-Signaling


  1. Surgical Resection
  2. External Beam Radiation Therapy
  3. Chemotherapy
  4. Ongoing Clinical trials


  1. Aurora Kinase inhibitors
  2. Natural/Synthetic Compounds
  3. Gene therapy using Oncolytic Viruses
  4. Targeted Inhibitors
  5. Epigenetic Silencing
  6. Metabolic Pathway Targeting
  7. Apoptosis enhancing strategies
  8. Immunotherapy
  9. Combination Treatment





Thyroid cancer incidence is increasing at an alarming rate, almost tripling every decade. In 2017, it has become the fifth most common cancer in women. Though the majority of thyroid tumors are curable, about 2-3% of thyroid cancers are refractory to standard treatments. These undifferentiated, highly aggressive and mostly chemo-resistant tumors are termed as anaplastic thyroid cancer (ATC). ATC causes more than 40% of thyroid cancer-related mortality with an average life expectancy of 6-7 months from the time of diagnosis.  Owing to its dedifferentiated phenotype and lack of thyroid cell specific markers including Thyroid Stimulating Hormone Receptor (TSHR), Thyroglobulin (TG) and Sodium Iodide Symporters (NIS), ATCs are resistant to standard radioiodine ablation and hormone suppression therapies. Therapeutic regimes include surgery, external-beam radiation, and chemotherapeutic drugs. In the past decade, significant progress has been made in our understanding of ATC pathogenesis, characterizing novel molecular targets, and evaluating the clinical efficacy of promising drugs. Unfortunately, effective treatments remain limited.  This review provides a detailed overview of ATC, genetic aberrations and molecular pathways involved in the pathogenesis, current therapeutic modalities and promising future directions towards improving clinical management.

Thyroid cancer is the most common endocrine-related malignancy, accounting for more than 90% of endocrine cancers  (1)In 2017, 56,870 new cases are estimated in the USA constituting 3.4% of all new cancer cases (2). The majority of thyroid cancers originate from follicular thyrocytes leading to follicular thyroid cancer (FTC) and papillary thyroid cancer (PTC). Amongst these differentiated thyroid cancers (DTC), PTC is the most common, comprising about 80% of all thyroid cancers. Other less frequent cancers are FTCs, and parafollicular cell originated medullary thyroid cancers (MTC). The prognosis of differentiated thyroid cancers is excellent with >98% five-year survival. At the other end of the spectrum are undifferentiated/anaplastic thyroid cancers (ATC) that have a median survival of only six months. Because of its dismal prognosis, it is responsible for 40-50% of total thyroid cancer-related deaths in the USA. There is a similar thyroid cancer subgroup designated as Poorly Differentiated Thyroid Cancer (PTDC). However, unlike ATCs, PTDCs show some of the follicular structures and can partially produce thyroglobulin but lack other morphological markers of FTC/PTC (3).

Current ATC treatment options are largely ineffective as it is highly resistant to most therapies. As per the American Thyroid Association (ATA) guidelines, the primary line of therapy includes surgical resection, if possible, and external beam radiation therapy for local control. Though, total thyroidectomy with high-dose radiation therapy is associated with improved survival (4); second line treatment with systemic targeted therapies, single or in combination, are often employed.  The majority of the ATC patients manifest metastasis at the time of diagnosis. Hence, the efficacy of chemotherapy, targeted or combinatorial, is limited.

ATC often clinically presents as a large neck mass causing dysphagia, dysphonia hoarseness, stridor, and dyspnea due to obstruction of the trachea (5, 6). Diagnosis relies on fine needle aspiration (FNA) biopsy and can detect up to 90% of ATC. As thyroid nodules are common in the population, FNA based diagnosis needs to be improved to enhance the sensitivity and the specificity of detection of malignancy and to avoid unnecessary surgical intervention (7). False-negatives are often due to low cellularity and obscuring inflammatory and necrotic debris. Moreover, there is a lack of definitive molecular biomarkers to detect the thyroid cancer in FNA biopsies with high sensitivity. In this regard, a customized panel (Thyroseq) comprising of 12 genes with 284 mutational hot spots was shown to yield 99.6 % success rate by using targeted next generation sequencing, and thus holds promising future (8, 9) .

Due to its highly metastatic clinical characteristics, ATC tumors are automatically designated as stage IV tumors irrespective of tumor burden. The are sub-classified as IVA, IVB, IVC and IVD tumors depending on the extent of invasion in the surrounding tissues (10, 11). Pathologically, ATC cells are spindle-shaped, giant and squamoid cells, accompanied with high mitotic index, necrosis, hemorrhage and vascular invasion (12). Because of high vascularization, misdiagnosis with angiosarcoma is common. About 70% of ATCs invade surrounding tissues including fat, trachea, esophagus and larynx. The most common metastatic site in ATC patients are lungs, bone, and the brain (13).

The origin and development of ATC are still controversial. However, it is believed that ATC can arise de novo as well as from well-differentiated thyroid cancers (14). The majority (~90%) of ATC tissues show concomitant expression of foci of other thyroid cancer types – mainly PTC including tall cell variant and insular – suggesting that ATC can develop on a DTC background (15). Supporting this notion, Targeted expression of BRAF mutation (BRAFV600E) in mouse PTC models gradually induce dedifferentiation (16). Though the mechanism of dedifferentiation is not well understood; it is marked by events including chromosomal gains and deletions, and dysregulation of several signaling events including cell cycle and adhesion (17). Cells undergo several epigenetic and genomic changes which result in altered signaling pathways that contribute to phenotypic aggressiveness and metastatic potential of ATC cells.

Given the poor prognosis of this disease and limited efficacy of minimally evidence-based treatment options, clearly, new therapeutic strategies are necessary. Development of effective treatments has been hampered by the relatively small number of patients and a lack of definitive data on tumor etiology and molecular pathways of carcinogenesis. Therefore, the purpose of this review is to identify common mutations in the molecular pathways involved in carcinogenesis, and the current clinical therapeutic regimens being employed in ATC. With this information, we will introduce new and promising therapeutic options upon which future clinical trials could be built.


Genetic lesions and mutations are integral to ATC carcinogenesis. These genetic mutations result in the hyper-activation of pathways involved in cellular growth, proliferation, and metastasis and inhibition of processes such as growth arrest, differentiation, and apoptosis. The Cancer Genome Atlas Network performed a comprehensive analysis of the mutational landscape of 496 PTC tissue samples and classified PTC into molecular subtypes (18). However, very few such studies have been  conducted in ATC. The reasons for a dearth of genomic and mutational studies in ATC are the rarity of the disease and difficulties in separating tumor tissue from stromal elements (19). Also, ATC tumors (but not DTCs) are often tightly linked with Tumor-Associated Macrophages (TAMs) which likely perform metabolic and trophic functions required for tumor growth (20).  The high density of TAMs in advanced thyroid cancers (PTDC and ATC) correlated with invasion and decreased cancer-related survival (21). Because of the tight intertwining of macrophages around ATC cells, laser-based microdissection cannot be used to obtain pure ATC specimens for gene expression profiling. In a recent study, the mutational landscape of ATC was examined by whole exome sequencing (WES) in 22 ATC patient’s tissue samples. Mutations in mTOR, NF1, NF2, MLH1, MLH3, MSH5, MSH6, ERBB2, EIF1AX and USH2A were identified in ATC specimens but not in DTC or normal tissues (19).More recently, by employing ultradeep sequencing strategy with MSK-IMPACT cancer exome panel that includes 341 exons of known altered genes in human cancer, a comprehensive genomic investigation was performed in 84 poorly differentiated thyroid cancers (PTDC) and 33 ATC specimens (22). A 78-gene signature specific to M2 macrophages was used in the array to exclude the background contribution by TAMs. ATC specific genetic profiles exhibited differential expression of p53, Telomerase Reverse Transcriptase (TERT) promoter, SWI/SNF complex, Histone MethylTransferases (HMTs) and effector molecules from PI3K/AKT pathway. Clonal prevalence of mutations in the TERT  promoter (C228T and C250T) in ATC and PTDC, as compared to DTCs, may indicate a role in imparting immortality and aggressiveness to ATC cells (23).  Additionally, ATC patients harboring TERT promoter mutations along with BRAF or Ras mutations showed very poor survival (732 vs. 147 days,  = 0.03) (22). Lately, TERT C228T has been shown to correlate with BRAFV600E mutation and distant metastasis in ATC (24). Several other genetic mutations including β-Catenin (CTNNB1), Vascular Endothelial Growth Factor Receptor 1(VEGFR1), VEGFR2, KIT, MET, PI3KCA,And FOXA1 are reported in ATC pathogenesis (25, 26)In a recent study, gene expression analysis  exhibited various  epigenetic alterations such as frameshift deletions of HDAC10 and EP300, loss of SMARCA2 and fusions of MECP2BCL11A, and SS18in ATC specimens versus PTC/normal tissues (27).  An investigation using next generation sequencing revealed Axin1, PTEN and APC as de-differentiation specific genes, besides already known CTNNB1, PIK3CA and TP53 (28). These mutated genes are associated with signaling pathways involved in cell replication, migration, invasion, and angiogenesis, which can promote ATC tumorigenesis. Another study based on functional genomic mRNA profiling comparing 25 ATC specimens and 80 normal thyroid tissues identified mTOR, MET, WEE1, PMD1, MERTK, FGFR3, RARG, and ESR2 as potential therapeutic targets (29). Of note, these genes were selected on the basis of their known interactions with anti-neoplastic drugs, current drug use in humans, and association with biologic pathways known to be involved in ATC development.

Further molecular characterization of some of the differentially expressed genes led to the identification of Forkhead Box Protein M1 (FOXM1) gene which is associated with loss-of-function of p53 and hyper-activation of the PI3k/Akt/FOXO3A pathway (30).  Further, pharmacological inhibition of FOXM1 resulted in decreased tumor burden and reduced metastasis in an orthotopic mouse model of ATC. (31, 32). Likewise, Thioredoxin-interacting Protein (TXNIP) is a tumor suppressor gene and is downregulated in ATC. Restoring TXNIP function by using retrovirus-based transduction, showed an improved preclinical response in a mouse model. Further characterization revealed that TXNIP is transcriptionally controlled by Peroxisome Proliferator-Activated Receptor-γ (PPAR-γ) which is highly over-expressed in ATC and is also associated with aggressive behavior in DTCs (33).

Some of the most common aberrations in ATC can be categorized as follows:

a. Inactivating or Loss-of-function mutations: Point mutations that lead to loss of function of tumor suppressor genes are very common in ATC. The most commonly down-regulated tumor suppressor gene in ATC is TP53 (71-88%). The TP53 gene functions as the guardian of the genome and halts the cell cycle and proliferation in case of DNA damage, radiation, and other mutations. Loss of tumor suppressor function of p53 contributes to unchecked cell replication, accumulation of mutations in the genome and compounded genomic instability. (24) The TP53 gene mutation is common in ATCs, but not in DTCs including PTC and FTC (34).

PTEN is another tumor suppressor gene that is impaired in ATC. PTEN is a phosphatase that negatively regulates PI3k/Akt signaling. Inactivation mutation of PTEN can hyper-activate PI3k/Akt signaling and thereby promote cell proliferation and tumor formation. It is interesting to note that PTEN is not frequently mutated in sporadic human cancers and its deletion was discovered in a germline disease, Cowden syndrome wherein, patients are genetically more inclined to develop thyroid cancer, especially FTC. This suggested a possible role for this mutation in early thyroid carcinogenesis.  In thyroid cancer, PTEN inactivation can be caused by point mutation or promoter methylation, which progressively increases from benign thyroid adenoma (BTA) to FTC to ATC (35).

Recently, targeted massive parallel sequencing of 11 ATC samples revealed novel loss of function mutations in NF2KMT2D, and PKHD1 in 27%, 18% and 18% specimens respectively (36)However, their direct functional and phenotypic consequences remain to be elucidated.

b. Activating or Gain-of-Function Mutations: Activating point mutations in single nucleotide may result in a change of an amino acid, which can render the translated protein constitutively active. The classic example of such a gain-of-function mutation is BRAFV600E, wherein, substitution of valine with glutamic acid results in the ctivation of this serine/threonine kinase. BRAF is a key player in Mitogen-activated protein kinase (MAPK) pathway and BRAFV600E is the most common genetic alteration in PTC (~ 60%) and shows variable frequency in ATC specimens (~15-44%) (26, 37). Both wild-type BRAF and BRAFV600E can co-exist in the same PTC specimen suggesting that 1) it acts as a precursor lesion for PTC development and its function is not crucial in later events 2) it is not the primary driver mutation for tumor initiation but is required for PTC progression. The later notion is strengthened by direct association of BRAFV600E mutation with reduced Sodium-Iodide Symporter (NIS) expression due to the upregulation of DNA methyltransferase 1 (38).

Another activating mutation commonly found in ATC is in proto-oncogene, Ras, involved in MAPK signaling. Normally, it possesses intrinsic GTPase activity that converts active Ras (Ras-GTP) to inactive Ras (Ras-GDP) and thus can limit Ras activation by acting as a self-regulatory switch. Activating mutations in Ras result in hyper-activation of both MAPK and PI3k/Akt pathways which promote cell proliferation and tumorigenesis. Activating Ras mutations are most frequently found in FTCs but are also reported in approximately 50% of ATCs and are correlated with tumor aggression as well as poorer prognosis in ATC patients (39, 40). The Ras family includes three genes: HrasKras and Nras; and their oncogenic mutations are involved in early thyroid cancer progression. The common Hras mutation  in ATC nodules is  Hras61 (41).  Implantation of thyroid epithelial cells harboring Hras mutation resulted in a benign form of FTC- well-differentiated follicular thyroid adenoma (FTA) in mice. However, thyroid cells with a Kras mutation did not develop tumors even after a year, but in transgenic mice possessing both a Kras mutation and PTEN deletion aggressive FTC developed rapidly within weeks (42). Thus, it is quite conceivable that Ras mutations are involved in early benign thyroid cancer development but may need additional genetic alterations to transform to FTC and eventually to ATC.

Interestingly, BRAF and Ras mutations have been found to be mutually exclusive in ATC, either BRAF and TP53 or Ras and TP53 have been found toco-exist (19). This further strengthens the hypothesis that ATC may arise from well-differentiated thyroid cancers, either PTC or FTC, by accumulating additional mutations in TP53 and other genes. In fact, in a murine model, ATC tumors were generated by combining BRAFV600E mutations with either TP53 suppression, PTEN deletion or PIK3CA H1047L alteration (43, 44). In contrast, Ras mutations always coexist with EIF1AX mutations in ATC. EIF1AX is a member of the translation pre-initiation complex (PIC), and it is speculated that Ras-induced PI3k-Akt/mTOR signaling may provide a further cooperative benefit and play a pivotal role in the disease progression, and in generating specific tumor cell dependencies; thus, it merits further investigation (22, 45).

Some of the members of PI3k/Akt signaling pathway exhibit activating mutations in variable frequencies in ATC such as PI3KCA, Akt (10-23%) (35, 37). Other less common activating mutations were identified in exon 23 of Anaplastic Lymphoma Kinase (ALK) gene. The resulting alterations – L1198F and G1201E- were present in 11.1% of ATCs.  These activating mutations can significantly increase the tyrosine kinase activity of ALK which can further upregulate PI3k/Akt and MAPK signaling pathways (31).

c. Amplification and Copy Number Gain: Gene amplification and Copy number gain yield similar biological consequences but are slightly different. Gene amplification is a key event during oncogenic transformation characterized by multiplication of intra-chromosomal DNA segment culminating in hundreds of copies of a gene. However, Copy number gain is attained by cancer cells due to underlying genetic instability, aneuploidy, polyploidy or loss of telomerase activity. The degree of increase is higher is gene amplification as compared to copy number gain. These processes increase the levels of proteins that are involved in cell growth, survival, and proliferation. Besides point mutations, PI3KCA gene showed a gain in copy numbers in about 42% of ATC tissues (46). The frequency of amplification varies among different ethnic populations  (25, 46-48). Importantly, PI3KCA amplification was significantly correlated with AKT activation and showed increased frequency from benign thyroid adenoma (BTA) to invasive squamous cell carcinoma (35). In ATC, copy number amplifications were reported in several genes including Epithelial Growth Factor Receptor (EGFR), Platelet-derived Growth Factor Receptor (PDGFR) alpha, PDGFR-Beta, VEGFR1, VEGFR2, Kit, Met, Ras, BRAF, PIk3CA, PIk3CB, and Phosphoinositide-Dependent Kinase-1 (Pdk1)and to a lesser extent in Akt1, Akt2, and Receptor Tyrosine Kinase (RTK) genes (25, 49).

d. Chromosomal Rearrangements: Chromosomal rearrangements or translocations are governed by spatial positions of broken loci, recombination, and DNA repair elements (50). Rearrangements of genes provide selective growth advantage or aid in the initiation of tumor growth. One such chromosomal rearrangement that is well characterized in thyroid cancers is RET-PTC. RET is transcribed from chromosome 10q11.2 and due to translocation of a promoter of an unrelated gene, this tyrosine kinase, independent of ligand binding, remains constitutively active. RET/PTC fusion is very common is PTC and ATC, and can alter several processes such as activation of both MAPK/ERK and PI3k/Akt pathways (51). Moreover, RET/PTC rearrangement can also directly impair adenylyl cyclase activity (cAMP/PKA signaling) which regulates Thyroid Stimulating Hormone Receptor (TSHR) and NIS expression, thus rendering ATC patients refractory to radioiodine therapy (52).

Another commonly existing chromosomal rearrangement in ATC is PAX8 and PPAR-γ gene fusion that results in the formation of the PAX8-PPARγ fusion protein (PPFP) (53). PPARγ is a ligand-dependent transcription factor mainly involved in cell differentiation. The PAX8/PPARγ rearrangements are associated with good prognosis in FTC. Forced expression of PPFP in several ATC cells resulted in reduced cell growth with upregulation of miRNA-122 and miRNA-375, and inactivation of PI3k/Akt signaling. However, increased intrinsic NIS expression did not result in increased iodine uptake suggesting that the NIS was functionally impaired (54). However, PPARγ agonists still represent a potential therapeutic option for ATC patients because of their effect on angiogenesis. In a recent study involving one primary ATC tissue sample and three validated ATC cell lines, three unique fusions namely MKRN1-BRAFFGFR2-OGDH, and SS18-SLC5A1 were reported (27). The exact role of these fusion products in ATC pathogenesis are unknown and warrants further investigation.

e. Epigenetic Alterations: In ATC several genes are epigenetically dysregulated during the process of de-differentiation (55). During malignant transformation, cells undergo chromatin remodeling resulting in global epigenetic reprogramming by hypermethylation and increased deacetylation:

I) Hypermethylation: In ATC, enhanced histone methylation has been shown to suppress functions of several genes involved in cell cycle regulation, cell adhesion, apoptosis, and differentiation. EZH2 is an example of one of such overexpressed histone lysine methyltransferases in ATC. EZH2 mainly silences thyroid-specific transcription factor, PAX8 leading to an aggressive phenotype and poor survival (56). Other genes, which are suppressed by histone methylation are p16, INK4A, DAPK, UCHL1, MGMT, TSHR, PTEN, and MAGE-A4 (49, 57). Repression of these genes results in unchecked growth, replication, and resistance to chemo- and radio-iodine therapy.

II) Increased Deacetylation: Histone Deacetylases (HDACs) are a subset of histone modification enzymes, which result in activation of proto-oncogenes. Deacetylation results in increased expression of various crucial molecules involved in pathways such as MAPK/ERK,  PI3K/AKT, and Epithelial-Mesenchymal Transition  (EMT) which contribute to dedifferentiation, migration, and invasion (58). Several studies showed that inhibition of HDACs resulted in induction of differentiation genes such as E-Cadherin (59), NISThyroid Peroxidase (TPO)Thyroglobulin (TG) and Thyroid Transcription Factor -1 (TTF-1) (60, 61). Thus, targeting HDACs have emerged as a promising therapeutic strategy for ATC clinical management.

f. MicroRNAs Aberrations: MicroRNAs (miRNA) are small (19–25 nucleotides) RNA molecules that are involved in RNA silencing and regulation of post-transcriptional gene expression. miRNAs can act as both negative and positive regulators of genes involved in cell proliferation, survival, apoptosis, and growth (62). These miRNAs are putative molecules for diagnosis, detection, and targeted therapy. Recently, the downregulation of two miRNAs (miRNA-150 and miRNA-23b) exhibited their clinical utility as the prognostic and diagnostic markers for conventional PDTC and oncolytic (Hurthle type) PDTC which are slightly different in their cytopathology. Upregulation of miRNA-20A, which is differentially expressed in ATC in comparison to DTCs and normal tissues, was shown to contribute to ATC progression, and its knockdown resulted in reduced cell proliferation and tumor growth (63). Another miRNA, miRNA-30d is a negative regulator of Beclin-1, which is a key player in autophagy. Downregulation of miRNA-30d altered the ability of cells to undergo autophagy and conferred resistance to cisplatin in ATC cells (64). The miR-200s is a family of miRNAs which are involved in EGFR mediated EMT and their repression in ATC cells promoted their invasion (62). Restoration of miRNA200s resulted in induced expression of the epithelial cell marker, E-cadherin and a concomitant reduction in the mesenchymal marker, Vimentin (65) in ATC cells. Other miRNAs such as miRNA-25, miRNA-125 and miRNA-let-7, which are mainly involved in regulating cellular proliferation, chromatin remodeling and apoptosis are downregulated in ATC. Other differentially expressed miRNAs in ATC include miRNA221/222, miRNA17-92 cluster, and miRNA146a/b; these miRNAs mainly target tumor suppressors PTEN and P21 (66). Silencing of miRNA-21 has been shown to reduce stemness and promote apoptosis in ATC cells in vitro, marked by upregulation of differentiation markers including PDCD4p21NIS, and TG and down-regulation of pluripotency markers including Oct-4ABCG2, and MCL-1 (67). These studies indicate that miRNAs play an important role in ATC development and more comprehensive analysis is needed to understand their role in tumorigenesis and to design novel therapeutic approaches.


Accumulation of distinct multiple mutations culminates in ATC initiation and progression. These acquired genetic lesions affect several cellular processes and signaling pathways which impart ATC cells with unlimited growth potential, metastatic ability, and resistance to various therapeutic modalities. Delineation of underlying signaling mechanisms has helped in developing several inhibitors for targeted therapies in the past few decades. Though ATCs are highly heterogeneous tumors in nature and each lesion undergoes a unique genetic evolution, some of the frequently dysregulated pathways in ATC are discussed below:


a. p53 Pathway: The TP53 gene is well-characterized tumor suppressor gene that is frequently mutated in ATC tissues as compared to other differentiated forms of thyroid cancer (68). The p53 pathway blocks the cell proliferation under genotoxic and non-genotoxic stress conditions and induces DNA repair, growth arrest and apoptosis. Under non-stressful conditions, the level of p53 protein is downregulated via the binding of proteins (negative regulators) such as MDM2, COP1, PIRH22 or JNK that promote p53 degradation via the ubiquitin/proteasome pathway (69). As most of these genes are up-regulated by p53, this forms a regulatory loop that will keep p53 level very low in the normal cells. Under stress conditions, p53 gets activated in two ways: a) p53 protein level is increased via the inhibition of its interaction with Mdm2 and the other negative regulators. b) p53 transcription and translation are upregulated by a series of acetylases and kinases that can result in p53 accumulation. Upon stimulation, p53 (a transcription factor) translocates to the nucleus and activates the transcription of genes involved in cell cycle arrest and apoptosis including p21Bax, and Puma (70). The p21 interacts with cyclin-dependent kinases (CDKs) and induces cell cycle arrest, and Bax and Puma orchestrate to induce p53 dependent apoptosis (Figure 1). In ATC, the p53 pathway is impaired due to either loss of function mutations in TP53 gene (point mutations/deletions in several exons) (68), or gain of function mutations in its negative regulators such as HMGA1 and MDM2 (71, 72). Mutations in other E3 ubiquitination ligases such as Pirh1 and Cop1 have not been yet reported in ATC but is known in other aggressive cancer such as metastatic prostate cancer and lung adenocarcinoma (73). Functional impairment of p53 pathway during DTC to ATC transition results in unchecked cell division, genetic instability, and aneuploidy which contributes to the aggressive features and de-differentiation in ATC. As stated earlier, BRAF mutation and loss of TP53 cooperate to facilitate the progression from PTC to ATC. However, additional unknown events might also be involved as a latency period was observed before initiation of ATC growth (43). Recently, a transcription factor, POZ-Zinc finger protein (PATZ1) was found to be differentially down-regulated in ATC, as compared to PTC and normal thyroid tissues. Restoration of PATZ1 activated p53 signaling and restoration of its functional effects such as reduced cell migration and invasion (74) were noted. Further studies indicated that PATZ1 interacted with p53 and regulated downstream signaling involved in cell cycle and apoptosis; hence, it represents an alternative target in ATC tumors having a dysfunctional p53 protein (75).

The TP53 mutations are crucial for DTC-ATC transition as other aberrations such as BRAFV600E (point mutation), PTEN deletion or RET-PTC fusion are not sufficient to induce ATC tumors. Although BRAFV600E mutation was enough to develop PTC in mice, additional TP53 alterations resulted in PTC to ATC transformation (76, 77). Interestingly, BRAF and TP53 mutations coexist in the majority of ATC tissues, especially when PTC was the precursor lesion. Similar findings have been reported in mouse studies involving RET/PTC-driven PTC and PTEN deletion driven FTC induction in which loss of TP53 was required for transformation into more aggressive thyroid cancers (78, 79).

b. RAS/RAF/MAPK Pathway:  Classical MAPK signaling is essentially involved in cellular growth and proliferation, and is often hyperactivated in several tumors.  It involves sequential phosphorylation of Rafs (BRAF) by Ras (Kras) proteins, which, in turn, activates the downstream MEK (MEK1, MEK2, AND MEK3), and eventually the effector MAPKs such as ERK and p38. These activated transcription factors (ERK/p38) translocate into the nucleus and activate genes such as VEGFA, Matrix Metalloproteinases (MMPs), Prohibitin, Vimentin, MET, NF-κB, Hypoxia-inducible Factor (HIF)1α, EG-VEGF, Transforming Growth Factor-β (TGF-β), and Thrombospondin 1 (TSP-1) (80). These genes promote tumorigenesis by activating pathways such as cell proliferation, invasion, migration, and angiogenesis (Figure 2).

Hyperactivation of MAPK signaling also modulates extracellular microenvironment by making it pro-tumorigenic via autocrine and paracrine interactions. TSP-1 is one such MAPK-activated protein that interacts with integrins, MMPs and cytokines, and promotes tumor dissemination (81). In BRAFV600E mutant ATC cells, Tsp-1 resulted in altered expression of integrins such as ITGα3, α6, and β1 (82). Another chemokine, TGF-β produced as the result of hyperactivation of MAPK pathway is mainly found in the periphery of ATC specimens and is believed to be involved in tumor-stroma interactions (83). TGF-β promotes inflammation in the tumor microenvironment leading to enhanced oxidative stress, which can further activate MAPK signaling (84). It is plausible that TAMs also produce TGF-β and this MAPK/TGF-β – loop can help ATC tumors to become self-sustainable and also help in tumor dissemination. Apart from its role in modulating tumor microenvironment, BRAFV600E mediated MAPK signaling also promotes dedifferentiation by repressing NIS expression via BRAFV600E/TGF-β loop.  Inhibition of TGF-β/SMAD signaling could rescue the BRAFV600E induced NIS repression, but NIS was dysfunctional in its ability to promote iodine uptake. Thus, other mechanisms are involved in maintaining NIS functional integrity. Furthermore, targeting TGF-β1 was shown to induce mesenchymal-epithelial transition (MET) resulting in reduced cell migration and invasion of ATC cells (83-85).  Also, targeting TGF-β1 inhibited ATC tumor growth by activating ERK1/2/NF-κB/Puma signaling (86). In summary, it is apparent that tumor-stroma interaction is crucial for ATC development, and MAPK signaling is intricately involved in this process.

Tumor-stroma interaction is not restricted to cytokine-mediated signaling but also includes cell-cell interaction. Fibroblasts which are the major components of stroma can also promote tumor progression. Implantation of thyroid cancer cells expressing two isoforms of Fibroblast Growth Factor Receptor (FGFR) 2 – FGFR2-IIIb and FGFR2-IIIc – exhibited a significant reduction in tumorigenic potential. However, in fibroblast cells, forced expression of same isoforms resulted in more aggressive tumor growth. Further, co-implantation of thyroid tumor cells and fibroblasts expressing the same isoforms did not affect tumor growth. In contrast, co-implantation of FGFR2-IIIb expressing epithelial cells with FGFR2-IIIc expressing fibroblasts augmented tumor progression (87). A clear understanding of such tumor-stroma interactions offers new opportunities for developing novel therapeutics.

c. PI3K/Akt/mTOR Pathway: This signaling cascade is critical for many cellular functions including cell growth and proliferation. Upon growth factor binding (e.g. insulin-like growth factor 1), the signaling is initiated by the activation of PDK1 by Phosphatidylinositol-3-Kinase (PI3K) mediated conversion of Phosphoinositol diphosphate (PIP2) into Phosphoinositol triphosphate (PIP3). PDK1 activation, in turn, phosphorylates Akt leading to its activation. Activated Akt (pAKT) exerts its biological functions by phosphorylating downstream effectors such as mTOR, Bad, p21 and Caspase-9. Also, RAS can cause PI3K activation by binding to PI3K, which renders it constitutively active. The pAkt can promote tumor growth and metastasis by 1) inhibiting autophagy-mediated through mTOR, 2) inhibiting apoptosis through phosphorylating Caspase-3 and Caspase-9, 3) controlling cell cycle through phosphorylation of FOXO-1, 4) promoting cell invasion through regulation of MMP-2 expression and 5) inducing angiogenesis by upregulating the expression of transcription factor, HIF1α and consequently activating VEGF (Figure 3) (80). Other mutated members of this pathway in ATC are PPARγ and PDK-1.

PTEN is a phosphatase that catalyzes the conversion of PIP3 to PIP2 and hence negatively regulates PI3k/PDK1/Akt signaling. Inactivation mutation of PTEN can also have severe negative consequences and promote cell proliferation and tumor formation. Ras/MAPK signaling is primarily dysregulated in PTC whereas PI3k/Akt pathway has a central role in FTC pathogenesis. Intriguingly, PI3K/AKT pathway is highly dysregulated in FTC but not in its benign counterpart (FTA) suggesting a crucial role for this signaling pathway in FTC by promoting vascular and capsular invasion (88). However, the transformation of FTC to ATC involves other aberrations such as p53 inactivation and CTNNB1 mutations, in addition to sustained hyperactivation of PI3k/Akt signaling.

d. Wnt-β-catenin Pathway. Several studies have reported hyperactivation of Wnt signaling in PDTC and ATC but not in DTC. Wnt/β-catenin/Shh pathway is mainly involved in embryogenesis and can also promote cancer by the induction of EMT. In the absence of Wnt ligand, β-catenin exists in a multi-protein complex, which is inactive. Binding of Wnt to the receptor, Frizzled (Frz) causes activation of Disheveled (Dsh), which in turn, results in dissociation of the complex containing Axin1, β-catenin, APC, and GSK3β. Free β-catenin can then translocate to the nucleus and promote transcription of several genes involved in EMT and cell division. Although, β-catenin (CTNNB1) is mutated in about 26% of ATC specimens, other members of this signaling pathway that are mutated in ATC are APC (9.0%) and Axin1 (89%). Two of the target genes of Wnt/β-catenin pathway namely, Cyclin D1 (27.1%) and c-MYC (59.1%), are highly overexpressed in ATC (Figure 4) (89).

E-Cadherin, an epithelial cell-specific adhesion molecule, forms a complex with β-catenin and α-catenin and binds to cellular actins to provide polarity to epithelial cells and thus promotes cellular integrity and adhesion. Mutation in β-Catenin (CTNBB1) can prevent formation of this complex and result in the transformation of keratin-dominant epithelial morphotype to vimentin-dominant mesenchymal morphotype. Forced over-expression of E-Cadherin can reverse this process and inhibit cellular migration (90). Hence, targeting Wnt/β-catenin pathway might be a potential approach for the development of therapeutics.

e. EMT-MET Transition: Epithelial-mesenchymal transition (EMT) is an integral part of ATC pathogenesis. It contributes to tumor dissemination and migration. Mesenchymal-Epithelial Transition (MET) is required during the formation of new metastatic secondary tumors. Mobile disseminated tumor cells, which have a mesenchymal phenotype, change back to an epithelial morphotype that is essential for adhesion and establishment of a new tumor. Activation of Wnt/β-catenin signaling causes induction of transcription factors as SNAI1 (Snail), SNAI2 (Slug), Zeb and Twist. These MET inducers cause reduction of E-cadherin, induction of Vimentin and MMPs, which results in the loss of cell polarity and adhesion while acquiring migratory mesenchymal phenotype by epithelial cells. It was shown that there is a derangement of the E-cadherin/Catenin complex during the transformation of DTC to ATC, suggesting the potential significance of dysregulated Wnt and EMT signaling in ATC pathogenesis (91). Also, Twist is highly expressed in ATC and is associated with cellular invasiveness and chemoresistance against several drugs including Cisplatin and Staurosporine (92).

f. NF-κB Signaling: This signaling has a central role in inflammation as well as cancer.Ligand binding to growth factor receptors [e.g. Insulin-like Growth Fazctor Receptor (IGFR)], cytokine receptors (e.g. TNFR and IL-1R), CD40L and Toll Like Receptors (TLRs) can cause NF-κB activation. NF-κB is retained in the cytosol in an inactive form.  Depending upon the specific ligand receptor interaction, different kinases including Akt, NIK, CK2, Pkc, Rsk, GSK-β2, etc. are activated. These kinases can phosphorylate Inhibitor of κB (IκB) and mark them for proteasome degradation. Freed NF-κB translocates to the nucleus where it acts as a transcription factor to promote inflammation, cell survival, growth, and proliferation. The connecting link between NF-κB signaling and cancer is through apoptosis inhibition and MMPs regulation. Particularly, in thyroid cancer, BRAFV600E activated MAPK signaling can directly phosphorylate IκB and thereby sustain NF-κB activation.  NF-κB can trigger the transcription of MMP9 which helps in the dissolution of the extracellular matrix and promotes metastasis (93). It can also enhance MMP9 enzymatic activity via Neutrophil Gelatinase-associated Lipocalin (NGAL) (94). Additionally, NF-κB can inhibit apoptosis by 1) upregulating anti-apoptotic molecules such as c-IAP-1, c-IAP-2, and X-linked Inhibitor of Apoptosis (XIAP) (95), 2) inducing the expression of TNF-α receptor family adaptor proteins (i.e. TRAF-1 and TRAF-2) leading to enhanced cell survival and angiogenesis, 3) promoting the expression of anti-apoptotic protein, Bcl-2, and 4) upregulating tissue inhibitor of metalloproteinases (TIMP-1), which further binds to its receptor CD63, and activates downstream Akt signaling (96).

Although inflammation is generally associated with immune responses against pathogens, uncontrolled and chronic inflammation can significantly increase the risk of cancer including thyroid cancer. The presence of inflammatory cells especially M1 macrophages, chemokines, and cytokines in tumor microenvironment show a close link between carcinogenesis and inflammation (97). In this regard, NF-κB can play a determinant role by upregulating the expression of chemokine receptor CXCR4 in ATC cells to which stromal-cell-derived factor1 (SDF-1) can bind and increase cell growth. Thus, NF-κB imparts a paracrine growth potential to ATC cells by regulating CXCR4 expression (98).  Another inflammation related axis, CCL20/CCR6/ NF-κB/MMP-3 was recently demonstrated in ATC cells. Chemokine CCL20 upon binding to the receptor CCR6, which are over-expressed in ATC cells, could activate NF-κB and cause enhanced transcription and secretion of MMP-3 (Figure 5). Thus CCL20/CCR6 interaction can promote cell migration and invasion through NF-κB activation (99).  Also, in 122 PTC patient’s specimens, NF-κB (particularly RelA) nuclear localization was found in 74.6% ATC tissue specimens and was strongly associated with high proliferation index (P=0.045) suggesting its possible role in tumor growth and aggressiveness of PTC after tumor transformation (100). NF-κB has also been shown to support oncogenic potential and resistance to drug-induced apoptosis in ATC cells by upregulating miRNA-146a (101). Further, NF-κB activation is also observed post combination (radiation and docetaxel) treatment in ATC cells, and its transient blocking along with combination therapy showed improved results in mouse orthotopic model (102). In conclusion, NF-κB is crucial for ATC progression and represents a novel target for therapeutic development.

g. Notch Signaling: Notch signaling is implicated in a variety of cellular processes including cell replication, differentiation, apoptosis and regulation of other signaling modules. Interestingly, Notch expression is significantly reduced in ATCs relative to the levels of its expression in PTCs and FTCs. Upon ligand binding (i.e. Delta-like ligand (Dll)-1, 3, and 4, Jagged1 or 2) notch receptor is cleaved by γ-secretase realeasing Notch intracytoplasmic domain (NICD) which can translocate to the nucleus where it binds to ubiquitous transcription factor, CBF1, Suppressor of Hairless, Lag-1 (CSL) and forms a complex. This complex can subsequently activate the transcription of several genes including p21c-MYXHER2 and Cyclin D1 (103). Expression of exogenous Notch-1 in thyroid cancer cells which exhibit reduced Notch-1 expression could facilitate re-differentiation and increase NIS and TPO expression without affecting the expression of TG gene (104). In normal thyrocytes, Notch-1 mediates their proliferation and differentiation by activating a downstream effector Hes1. Inactivation of Notch signaling seems to be a contributing factor in the acquisition of ATC-like characteristics, and its functional restoration might help in improving the current therapeutics.

h. Cross-Signaling: There is almost always cross-tALK between different signaling pathways. Perhaps, the involvement of more than one signaling process helps cancer cells to thrive in a stressful microenvironment, attain high growth rate, metastasize and develop resistance to therapy. In ATC, PI3k/Akt and Wnt/β-catenin pathways cooperatively promote tumor growth. In particular, pAkt can phosphorylate GSK3β resulting in its inactivation. Once inactivated, it no longer can sequester β-catenin and allows its free translocation to the nucleus. Additionally, RET-PTC (tyrosine kinase) can directly activate Wnt signaling either by phosphorylating β-Catenin or by activating the PI3k/Akt signaling pathway (93)Taken together, it seems that ATC cells undergo a series of genetic alterations in the course of their evolution from either DTC or normal thyrocytes. ATC tumors also show some level of oncogene addiction and because of a high degree of genetic instability, ATCs quickly modify their proteome repertoire to acquire resistance. Thus, a more comprehensive analysis of transcriptome/proteome may help in designing more efficient combinatorial therapeutics to improve the clinical management of ATC patients.


As per the ATA guidelines, multimodal treatment is recommended for ATC including surgical resection, hyper-fractionated accelerated external beam radiotherapy, followed by a combination of chemotherapies and palliative care (105). Despite multi-armed treatment, median survival amongst patients with ATC is six months. ATC chemoresistance is mainly attributed to Cancer Stem Cells (CSCs) in thyroid tissues, which were described as cells expressing the pluripotency marker Oct4, endodermal marker GATA4, and HK4 and thyroid cell specific TTF1 and Pax (106-108). These CSCs express ABCG2 and multi-drug-resistant 1 (MDR1) transporters which confer resistance to Cisplatin and Doxorubicin.  Further characterization of CSCs in ATC revealed that Sox2 is the determinant factor that confers chemoresistance to ATC cells by regulating ABCG2 expression (109). Owing to the failure of single-agent chemotherapy, combinations of Paclitaxel, Cisplatin, Doxorubicin, Pegfilgrastim and Docetaxel are administered to ATC patients (10). In the past decade, several novel drugs have been evaluated to improve clinical outcomes. However, most of the clinical studies are limited in assessing the clinical outcomes due to both the rarity of the tumor and limited patient survival. Clinically, adjuvant radiation and chemotherapy are usually co-administered in ATC patients after surgery. The second line of treatment includes targeted therapies such as tyrosine kinase inhibitors, anti-angiogenic drugs, and agonists and multi-kinase inhibitors for BRAF, mTOR, and ABR-BCL.The current mainstays of treatment for ATC are discussed below:

a. Surgical Resection: Surgical management is generally precluded for patients with anaplastic thyroid cancer due to advanced stage at the time of presentation (110); however, complete surgical extirpation is recommended for localized disease that is amenable to resection without excessive morbidity. If the tumor is limited to the thyroid parenchyma, thyroidectomy with wide margins is recommended, especially if the tumor reflects good prognostic features including unilobar disease, diameter <5cm, and without nodal spread, for which lobectomy alone may be able to be performed (111). In fact, in the rare instance of a small, unilocular contained mass, total thyroidectomy appears to offer no survival advantage over lobectomy and carries increased morbidity (112, 113). Interestingly, in the Mayo Clinic series over 50-years, incomplete resection was no worse than negative margins in regard to overall patient survival. This is likely due to the overall poor prognosis and difficulty in local control even with surgery for this aggressive disease. Regardless many still advocate for total thyroidectomy and central node dissection, and current guidelines recommend this approach if R0 (microscopically negative resection) or R1 (grossly negative, microscopic positive) resection can be achieved (113, 114).

Complete resection is challenging often due to tumor size, extra organ growth extension, and local invasion. The goal of surgery is for a margin-negative R0 resection. Pre-operative evaluation with high-quality fine-cut cross-sectional imaging and ultrasound is necessary to determine tumor extent and the possible involvement of the carotid artery, jugular vein, vagus nerve and its branches, trachea, esophagus, sternocleidomastoid and strap muscles. If there is a concern for recurrent laryngeal nerve involvement, speech changes may already be present. However, laryngoscopy can be invaluable to assess vocal cord mobility and bronchoscopy to assess tracheal involvement. If one recurrent laryngeal nerve is already involved, then it is of utmost importance that the contralateral nerve is preserved and/or only ipsilateral lobectomy performed, if possible. If contralateral resection is necessary to obtain negative margins, the use of a nerve stimulator may enhance recurrent laryngeal nerve identification and preservation during surgery, though this is surgeon-dependent. Furthermore, imaging is critical to assess for metastatic disease, in which case resection should not be performed in the absence of airway compromise.

After the proper assessment, if resection can be performed, patients have improved outcomes even if positive margins result. The radical resection should be to obtain a negative margin, as stated. However, laryngectomy is usually discouraged due to the likelihood of persistent disease and the severe morbidity associated with this procedure.  Current recommendations, based on the only moderate quality of evidence, advise for lobectomy, total, or near-total thyroidectomy, with therapeutic lymph node dissection (10). The approach involves standard lifting of subplatysmal flaps and division of the deep cervical fascia in the midline to expose the underlying gland. Involvement of the strap muscles necessitates a division of the muscles, which should be performed en bloc with the thyroid.  With radical surgery to obtain wide negative margins, and due to the infiltrative nature of this cancer, parathyroid glands may need to be sacrificed. In these instances, efforts should be made to identify and preserve all uninvolved parathyroid glands and to confirm histology, mince, and re-implant at the end of the case to prevent severe hypocalcemia.   Central and lateral lymphadenectomy is performed at the same time as the resection, and additional soft tissue, fascia, muscle, or veins should be taken en bloc if involved.

Tracheostomy or palliative resection is also sometimes necessary due to a tracheal impingement in order to manage airway compromise or esophageal obstruction. As has been mentioned, chemotherapy alone is ineffective in controlling this disease. However, a study by the Swedish Anaplastic Thyroid Cancer Group combined Adriamycin to induce radio-sensitivity combined with 3 weeks of radiation followed by debulking surgery and sandwiched adjuvant radiation (115). With this protocol, some previously un-resectable tumors could be converted to resectable tumors. Though there were individual patient successes, the overall improvement in local control and overall survival remains to be demonstrated.  Clearly, surgery has a role in the treatment of this disease, particularly for small, localized tumors, and in the palliative setting to avoid suffocation; however, optimal outcomes should include multimodality treatment strategies.

b. External Beam Radiation Therapy: Due to the lack of iodine uptake of poorly differentiated ATC cells radioactive iodine (131I) therapy is ineffective in localizing radiation to the gland and thus external beam radiation therapy is the current option for this treatment modality. In a study of the National Cancer Database, radiation therapy was found to be associated with improved overall survival in a cohort of ATC patients (116). The contribution of high-intensity external beam radiation therapy to improve survival (>40 Gy) relies on the ability to adequately resect the tumor, which as mentioned above, is only possible in a minority of cases due to locally aggressive growth patterns. In a recent meta-analysis including 17 retrospective studies of 1147 patients, it was concluded that adjuvant radiotherapy helps in prolonging the survival of ATC patients. The results showed that post-operative radiotherapy significantly improved the survival in patients with resected tumors versus patients with surgery alone (HR, 0.556; 95% confidence interval, 0.419–0.737; p < 0.001). Moreover, it was also found that patients with stage IVA (HR, 0.364; p = 0.012) and IVB (HR, 0.460; p = 0.059) disease may derive a survival benefit from post-operative radiotherapy, whereas stage IVC patients may not (117).  The major challenge in analyzing the advantages of adjuvant radiation is the inherent time bias, as many patients studied already have extremely limited survival at diagnosis.  Considering the aggressiveness of ATC and time constraint in terms of treatment response and overall survival, the efficiency of high dose (54 Gy) short-term (3-4 weeks) radiation was evaluated. The study demonstrated comparable benefits as that of the standard radiation treatment (40 Gy for 5-6 weeks) (118). A combination of radiation and photothermal therapy was investigated in an orthotopic mouse model of ATC using polyethylene glycol-coated [64Cu]CuS nanoparticles. Radiation was provided from 64Cu and cytotoxicity was induced by the plasmonic/photothermal property of CuS.  Significant improvement was observed in overall survival by using this single platform dual therapy (119).  Likewise, a combination of radiations with Vermurafenib (BRAFV600E inhibitor) showed improved therapeutic control in BRAFV600E mutant thyroid cancer (120). Hence, radiation alone or in combination with chemotherapy is useful both in the adjuvant setting and for patients with unresectable disease.

C. Chemotherapy: In ATC cells, the sensitivity of several chemotherapeutic drugs including Paclitaxel, Docetaxel, Adriamycin, Nedaplatin, Cisplatin, Carboplatin, Etoposide, 5-fluorouracil (5-FU), Mitomycin C, and Cyclophosphamide have been tested. Paclitaxel showed the maximum inhibition rate in vitro (121). In a multi-centered, non-randomized clinical trial, conducted in Japan, the efficacy of weekly administration of Paclitaxel without radiation therapy was evaluated. The observed response rate was 21%, and the clinical benefit rate was 73% with median time to progression of 1.6 months. Long-term survival was seen in patients who underwent surgery (122). Though Paclitaxel is the most effective chemotherapeutic drug, chemo-resistance is fairly common in ATC patients. One of the reasons for Paclitaxel resistance in thyroid cancer is TAMs. TAMs occupy 50% tumor volume in ATCs. Mutations like BRAFV600E in advanced PTCs can induce expression of chemo-attractants such as CSF-1 and Csl-2in cancer cellswhich can further increase TAMs density and promote tumor progression (123).  It was shown that targeting CSF-1/CSF-1R pathway in TAMs may restore the sensitivity of thyroid cancer cells to paclitaxel (124). In another investigation, Jak/Stat5 inhibitors have shown to induce cell death in Paclitaxel-resistant cells (125). Hence, chemotherapy is a feasible and reliable class of drugs to target local cancer. However, subsequent novel and additional interventions are necessary to overcome the acquired resistance.

Multi-targeted kinase inhibitors (MKIs) are another category of chemotherapeutic drugs which have been extensively evaluated in clinical settings in advanced, metastatic, and radio-iodine refractory thyroid cancers (126). MAPK signaling is integral to ATC progression and possesses some of the promising molecular therapeutic targets. Drugs targeting Raf/Ras/MAPK signaling include BRAF inhibitors (Vemurafenib/PLX4032), MEK inhibitor (Selumetinib/AZD6244) and several other multi-kinase inhibitors (MKIs) such as Sorafenib, Axitinib, Pazopanib and Sunitinib (Table1). These inhibitors have been evaluated in preclinical models as well as in clinical trials and have shown some encouraging results (Table 2). Of particular, Sorafenib showed partial responses with progression-free survival (PFS) of about five months in phase III clinical trial in ATC patients. Patients exhibited manageable toxicity in comparison to placebo (127). However, most of the patients experienced a relapse of the disease suggesting the requirement of combination with other targeted therapies to improve outcomes. In this context, in advanced DTC patients who were unsuccessfully treated with Sorafenib, salvage therapy using Sunitinib, Pazopanib, Cabozantinib, Lenvatinib, and Vemurafenib have been tested. With salvage therapy, partial response (PR) was observed in 41% (7/17) patients suggesting a synergy of these drugs with Sorafenib, (128). In an attempt to improve the specificity of Sorafenib, it was chemically loaded in Poly-lactic-co-glycolic acid (PLGA) nanoparticles and combined with Cetuximab (EGFR inhibitor) (129). This formulation significantly improved the toxicity against ATC cells without affecting normal thyroid cells. Similarly, Maria-Graricella et al. demonstrated the implications of nanobubbles (NBs) and extracorporeal shock waves (ESWs) as a tissue-targeted delivery system for chemotherapy. Precise delivery of doxorubicin loaded NBs using ESWs resulted in drug GI50 reduction of about 40% in ATC cell lines (130). Another MKI, Lenvatinib has been evaluated in a phase III trial in metastatic DTCs and displayed 65% response rate (RR), with a median PFS of 18.3 months versus 3.6 months in placebo-treated patients (131). Recent clinical trials demonstrating the efficacy of these MKIs are shown in Table 2. Among the newly discovered MKIs, a class of “pyrazolo[3,4-d]pyrimidine” compounds (CLM29 and CLM24) that inhibits several targets such as EGFR and VEGFR, showed anti-proliferative and anti-metastatic effects in primary ATC cells and cell lines (132).

d. Ongoing Clinical Trials: Some of the potential map-kinase inhibitors have been tested in clinical trials and a list of recently completed clinical trials in advanced thyroid cancers is mentioned in Table 2. In advanced FTC, encouraging results were obtained by using selective, allosteric MEK 1 and MEK 2 inhibitor, Selumetinib (AZD6244, ARRY-142886). A subgroup of patients (12/24) reached a threshold for dosimetry radio-iodine treatment suggesting the induction of re-differentiation as a potent therapeutic modality for ATC patients as well. (133). Targeting mTOR signaling holds promise and a phase I/II clinical trial evaluating the mTOR inhibitor (Sapanisertib) is underway in anaplastic thyroid cancer patients. Several clinical trials in ATC are also underway to assess the combination of drugs that includes Selumetinib, Everolimus, Lenvatinib, Cabozantinib, Vandetanib and Vatalanib (134). A recently completed phase II/III clinical trial using a combination of Paclitaxel and Valproic acid showed no benefit in overall survival and disease progression in ATC patients (135). Four drugs that have been approved for advanced thyroid cancer treatment after completing phase III clinical trials include Vandetanib (ZETA), Cabozantinib (EXAM), Sorafenib (DECISION) and Lenvatinib (SELECT) (136, 137). Of note, several multi-kinase inhibitors (MKIs) such as Sorafenib, Axitinib, and Sunitinib, have been tested with limited efficacy (34, 138). Doxorubicin (topoisomerase inhibitor) showed initial, non-durable partial responses (~22%) followed by chemoresistance.

Aimed at improving the Paclitaxel efficacy, a phase I clinical trial using a combination of Paclitaxel and the PPARγ agonist Efatutazone demonstrated its safety and merited further evaluation (139). A Phase II clinical trial using the same combination in ATC patients is under way (Clinical trial No. NCT02152137).


So far, success in treating ATC patients has been very limited and thus there is continuing need to develop novel therapies. In this regard, several pre-clinical investigations have been carried out to explore the potential of various drugs, and some of the promising categories are discussed below:

a. Aurora Kinase inhibitors: Aurora kinases are serine/threonine kinases which are involved in chromosomal segregation and cytokinesis during mitosis. These kinases include three members: Aurora A, B and C. Apart from mitosis, these Aurora kinases are also involved in determining cell polarity, migration and invasion, and telomerase activity (140). Dysregulation of these Aurora kinases are frequently noted in ATC as compared to PTC or normal thyroid tissues and might cause uneven segregation and aneuploidy (141). Several Aurora kinase inhibitors including MK-0457 (VX-680), SNS-314 Mesylate, ZM447439, and AZD1152 have been tested in ATC cells and have shown significant cell cycle arrest and consequent reduction in growth and proliferation in vitro. Interestingly, treatment with one of the Aurora-A kinase inhibitors, MLN8054, resulted in 86% reduction in tumor volume in ATC xenograft mouse model (142). In a study, the combination of MLN8054 with Bortezomib (proteasome inhibitor) resulted in apoptosis and cell cycle arrest in ATC cells in vitro (143). Another Aurora kinase inhibitor/MKI, Pazopanib showed enhanced cytotoxicity in combination with paclitaxel; both drugs synergistically targeted uncontrolled cellular proliferation (144).

Another member of mitosis-related kinases, Polo-like kinase-1 (PLK-1), which regulates chromosomal segregation and is highly activated in ATC, was targeted using the PLK-1 inhibitor GSK461364AIt induced apoptosis and inhibited cellular proliferation in both mouse ATC allograft model and PDTC-derived cell lines (145).

b. Natural/Synthetic Compounds: Screening of potential drugs using compound libraries resulted in the identification of several novel inhibitors that can induce significant cytotoxicity in cancer cells including ATC.In a high throughput screening of 3282 drugs targeting mTOR, identified a compound called as Torin2, which showed a remarkable reduction in cellular proliferation in vitro and tumor growth and metastasis in a mouse model of ATC metastasis (146). In another study, quantitative high-throughput screening of thousands of potential compounds in three ATC cell lines (i.e. 8305C, C643 and 8505C) yielded a promising proteasome inhibitor named, Carfilzomib. Pre-treatment with Carfilzomib resulted in a reduction in metastases to distant organs and disease progression in mice (147). In another high throughput drug screening, an inhibitor of a highly over-expressed molecule in ATC, Survivin – YM155- showed a significant anti-tumor response by suppressing tumor growth and metastasis in mouse models (148). Also, a dual inhibitor, CUDC-101, which mainly targets MAPK pathway and histone deacetylation in ATC cell lines could suppress tumor growth and metastasis in vivo (149).  Anti-tumor effect of CUDC-101 is mediated by increased expression of p21 and E-Cadherin, and reduced expression of Survivin, XIAP, β-catenin, N-Cadherin, and Vimentin (149).

In a large-scale screening of 7000 compounds, Resveratrol was identified as an inhibitor of ATC proliferation in vitro. Treatment with Resveratrol-induced functional Notch1 protein expression and activated transcription of thyroid-specific genes including TTF1, TTF2, Pax8, and NIS (150). Also, Resveratrol treatment of CSCs isolated from ATC cell lines caused reduction of stem cell markers, confirming its potential to induce differentiation (151). Similar induction of differentiation was observed upon treatment with 1, 25 dihydroxy vitamin D3 (Calcitriol) and Valproic acid in CSCs (151, 152). Hesperetin was also identified as an inducer of differentiation and apoptosis in ATC cells by up-regulating Notch signaling (153). Using a similar approach, Chrysin was identified as a Notch inducer. Treatment of ATC cells with Chrysin resulted in increased levels of expression of NIS and HES1 with a concomitant reduction in cell growth as well as tumor formation in an ATC xenograft model. This tumor reduction was due to induced apoptosis as depicted by increased level of cleaved Poly ADP ribose polymerase (PARP) (154). Thus, these compounds may synergize with radioiodine therapy by inducing differentiation and thus warrant more comprehensive assessment to explore their clinical efficacy in ATC management.

c. Gene Therapy Using Oncolytic Viruses: It is a promising approach to restore the expression of tumor suppressor genes and to target oncogenes that cause tumorigenesis. Loss of NIS and p53 are key events during ATC pathogenesis. Restoration of NIS and p53 expression using an adenovirus-5 vector showed a significant increase in uptake of radioactive iodine (I125) and improved cytotoxicity in vitro and in vivo (155). The combination of Oncolytic viruses with small molecule inhibitors yielded promising preclinical results in ATC. For instance, a combination of the ATM (a Ser/Thr kinase involved in DNA replication) inhibitor KU55933 with oncolytic adenovirus dl922-947 improved its efficacy in ATC cells when treated with ionizing radiation (156). Recently, a novel approach using an oncolytic virus (dl922-947) showed a remarkable increase in the efficacy of PARP inhibitor Olaparib (157).  In another study by the same group, the efficiency of dl922-947 was further improved by combining it with a PARP inhibitor both in vitro and in vivo (157). Additionally, the oncolytic adenovirus dl922-947 was shown to affect the tumor microenvironment and consequently anti-tumor immune response by decreasing IL-8/CXCL8 and MCP-1/CCL2 expression in ATC (158). These are encouraging results in preclinical studies, and clinical utilization of oncolytic viruses is still evolving (159).

d. Targeted Inhibitors: Specific molecules which can inhibit the key signaling cascades in ATC are of significant interest.In this regard, receptor tyrosine kinases are promising targets as they are often hyperactivated in ATC. Some of the targeted tyrosine kinases which are over-expressed in ATC include EGFR, PDGFR, VEGFR, cMET (Hepatocyte Growth Factor Receptor) and RET tyrosine kinases (160) (161). All these molecules have been targeted and resulted in a favorable response in ATC patients. A list of target-specific inhibitors is given in Table 1.

Several PI3k/Akt/mTOR pathway inhibitors such as Everolimus, Temsirolimus, GSK69093, MK-2206, PX866, and ZSTK474 showed anti-cancerous properties with varying effects on cell proliferation. Everolimus showed safety in phase I clinical trial and is currently in phase II clinical trial (NCT02143726) in combination with Sorafenib (162)

Clinical efficacy of targeting BRAFV600E (Vemurafenib) has been limited (163) most likely due to the activation of PI3k/Akt and MAPK pathways by other mechanisms such as cMET activation. The cMET can directly activate Pdk-1 and Ras thereby bypassing BRAF mediated signaling.

NF-κB signaling is targeted by employing proteasome inhibitors to prevent IκB degradation. Carfilzomib is a potent proteasome inhibitor that was shown to induce apoptosis in ATC cells by upregulating p27 and downregulating anti-apoptotic molecule, ATF4 (147).Bortezomib is another proteasome inhibitor that showed promising results in combination with MLN8054 (Aurora kinase inhibitor) in ATC cells (143). Also, targeting CXCR4 by using antagonist (AMD3100) showed a reduction in ATC tumor growth in vivo.

OSU-53, a novel dual-AMPK activator/mTOR inhibitor, effectively inhibits growth in a variety of thyroid cancer cell lines including ATC and is most potent in cells with activating mutations in Ras or BRAF (164).

HIV protease inhibitor, Nelfinavir, which block both MAPK and PI3k/Akt signaling, induced DNA damage and inhibited cell proliferation in ATC cells in vitro (165)

A different category of molecular therapeutic targets includes Heat Shock Proteins (HSPs). These proteins are expressed in stressful conditions but are often over-expressed in cancers including ATC. Among all, HSP90 is a promising candidate molecule. HSP90 inhibitor (Radicicol) in combination with HSP70 inhibition induced significant apoptosis in ATC cells by suppressing Survivin (166). Two newly discovered HSP90 inhibitors, KU711 and WGA-TA, showed a remarkable reduction in stemness (i.e. aldehyde dehydrogenase (ALDH)+ and CD44+), migration and invasion of ATC cells in vitro, accompanied by downregulation of β-Catenin, BRAF, Akt, and pAkt(167).

e. Epigenetic Silencing: Epigenetic reprogramming is an intricate component of carcinogenesis. Epigenetic silencing by using Histone Deacetylases (HDACs) and Bromodomain and Extra-Terminal (BET) inhibitors represents a promising approach to induce cytotoxicity in ATC. In this regard, several HDAC inhibitors have been evaluated and have been shown to reduce stemness and re-differentiation in ATC cells. Trichostatin-A (TSA) and Suberanilohydroxamic (SAHA or Vorinostat) are two well-characterized HDAC inhibitors, which restored the expression of thyroid-specific genes such as NIS, TSHR, TPO, TG, and TTF-1 in ATC cells and increase their radioiodine uptake (61). Treatment with these HDAC inhibitors showed diminished CD33 expression, increased expression of thyroid-specific genes such as NISTg, and TTF1 in ARO cells. However, these HDACs inhibitors also resulted in increased expression of Oct4NanogSox2Klf4, and c-Myc which are mainly stem cells markers (168). Hence, these HDAC inhibitors have significant off-target effects. Thailandepsin A (TDP-A), a newly identified HDAC inhibitor, showed promising antiproliferative effects mediated by cell cycle arrest and activation of extrinsic apoptosis pathway in ATC cells (169). N-hydroxy-7-(2-naphthylthio) heptoxide (HNHA) is another recently discovered HDAC inhibitor that showed promising results in PTC and ATC cell lines by inducing caspase-dependent and ER stress-mediated apoptosis (170). Pugliese et al. showed that treatment with HDAC inhibitor, LBH589 can induce re-differentiation in the ATC cell lines BHT-101 and Cal-62, as indicated by increased NIS expression and radioiodine uptake (60). Further investigations are required to explore the therapeutic implications of these HDAC inhibitors and the maximum beneficial effects could be realized when they are used in combination with other targeted therapies.

BET inhibitors have recently emerged as potent epigenetic anti-cancer drugs. BET inhibitors exert their biological function by targeting the bromodomain and extra-terminal of BET proteins which interact with HDACs and regulate gene expression. Two recently discovered BET inhibitors, JQ1 and I-BET762, caused significant cell cycle arrest in ATC cells. By using chromatin immunoprecipitation (CHIP), these BET inhibitors have been shown to target, MCM5 (cell cycle regulator) in ATC cells. MCM5 was found to be highly over-expressed in PTC and ATC tissue specimens (171).  JQ1 was also evaluated in an ATC mouse model, ThrbPV/PVKrasG12D, and exhibited significant tumor reduction and enhanced survival. Further analysis revealed that JQ1 treatment reduced MYC expression and disrupted cyclin-CDK4/RB/E2F3 signaling indicating its promising applications as an anti-cancer drug (172).

f. Metabolic Pathway Targeting: Targeting metabolic pathways have emerged as a potential therapy for several cancers. However, very few studies have shown a modest response in ATC cells. The intervention of glucose analog, 2-deoxyglucose (2DG) renders ATC cells sensitive to radiation and chemotherapy (Cisplatin) but the observed effect was transient (173). In another study, an analog of Vitamin D3, 19-nor-2α-(3-hydroxypropyl)-1α,25-dihydroxyvitamin D3 (MART-10) was demonstrated to inhibit the migration and invasion of ATC cells by blocking EMT pathway (174). Microarray analysis of ATC versus normal thyroid tissues revealed significant distortion of fatty acid metabolism, and Stearoyl-CoA desaturase 1 (SCD1) was identified as a differentially expressed enzyme in ATC which was associated with tumor aggression. SCD1 targeting induced endoplasmic reticulum stress and consequently apoptosis in ATC cells, both in vitro and in vivo (175). Hence, this approach might help in improving the existing therapeutic interventions.

g. Apoptosis Enhancing Strategies: In thyroid cancer, an important apoptosis-inducing molecule, TNF-related apoptosis-inducing ligand (TRAIL), has been shown to potently and selectively kill cancer cells. TRAIL has emerged as an attractive molecular target owing to its specificity and lack of toxicity to normal cells. TRAIL resistance factors include activation of c-FLICE-like inhibitory protein (c-Flip) and reduced expression of Trail-R1 and Trail-R2 receptors on tumor cell surface. Interestingly, gene silencing of c-Flip and another key player in TRAIL-induced apoptosis MADD, can significantly improve the TRAIL sensitivity (176). Further, MADD knock-down and/or MADD dephosphorylation can also render differentiated thyroid cancer cells susceptible to TRAIL(177). Thus, targeting these TRAIL resistance factors will be an interesting approach to improve TRAIL sensitivity in ATC. In an independent study conducted by Gunda et al., TRAIL-R2 receptor agonistic antibody, Lexatumumab, was shown to induce apoptosis in HTH7 (ATC), BCPAP and TCP-1 cells. Interestingly, in Lexatumumab resistant cells harboring a BRAFV600E mutation, the combination with BRAF inhibitor (PLX4720) or PI3k inhibitor (LY294002) rendered the ATC Cells susceptible to apoptosis (178). In another investigation, combining TRAIL with the HDAC inhibitor, Vorinostat (SAHA) resulted in increased DR5 expression and consequent cell death (179). The combination of TRAIL with the HDAC inhibitor Valproic acid (VPA) also induced significant apoptosis in TRAIL-resistant, 8505C (ATC) cells by activating Jnk and phosphorylation of FADD and c-jun but not p38 (180). Also, HDAC inhibitors such as SAHA and MS-275 promoted apoptosis by preventing TRAIL degradation in thyroid cancer cells (181). In a recent attempt to understand the inherited TRAIL resistance in ATC cells, it was shown that miR-222 and miR-25 overexpression might result in a reduction in TRAIL protein and MEK4 expression (182).  Thus, targeting TRAIL/DR5 pathway to induce apoptosis may provide a promising approach to ATC therapeutics and warrant more comprehensive studies. Another class of apoptosis inducing agents consists of BCL (anti-apoptotic) inhibitors. The Pan inhibitor of Bcl family proteins, Obatoclax showed significant cell death in ATC cells in vitro. Interestingly, Obatoclax induced cell death was mainly through necrosis, concomitant with lysosome neutralization (183)

h. Immunotherapy: Chronic inflammation is associated with thyroid cancer. Moreover, the existence of tumor-associated macrophages within ATC tissues, the presence of NK cells and other tumor-infiltrating lymphocytes highlights the relevance of tumor-immune cells interaction in carcinogenesis (184).  TAMs (type M2) promote tumor growth in ATC by expressing high levels of immunosuppressive cytokines such as IL-10 and TGF-β1, thus promoting tumor development (20). Similarly, a recent study showed that BRAFV600E mutation is strongly associated with the expression of a co-stimulatory molecule Programmed Death Ligand-1 (PDL-1) in ATC clinical samples (P=0.015) (185). PDL-1 can bind to its cognate receptor PD1 expressed on T cells and down-modulate their function.  In a preclinical BRAFV600E/WT and  p53-/-mouse model, treatment with the BRAF inhibitor (PLX4720) and an anti-PD-L1 antibody resulted in significant tumor regression and strong immune responses (186). Immunotherapy is not clinically used for ATC management because of associated high tumor burden and a short duration available for treatment. Clinical trials using Pembrolizumab, an antibody against PD1 is under evaluation in phase II clinical trial (NCT02688608) in ATC patients.

i. Combination Treatment: Owing to the inherent and acquired chemoresistance of ATC cells to several drugs, a combination of different inhibitors is often used in preclinical and clinical scenarios to kill the aggressive tumors effectively.In this context,Allegri et al. have shown the synergistic effect of treatment with a Cdk inhibitor (BP-14) and an mTOR inhibitor (Everolimus) by demonstrating loss of cell viability and down-regulation of genes involved in EMT (187). Another combinatorial treatment with NF-κB inhibitor (Quinacrine) and Sorafenib showed improved survival in an orthotopic mouse model in comparison to vehicle treated and Doxorubicin-treated mice (188). In contrast, combining NF-κB inhibitors with taxane cytotoxic drugs and/or radiation therapy did not show any synergistic effect on ATC cells (102). Another novel strategy targeting ERK pathway by combining MEK inhibitor-Trametinib and multi-kinase inhibitor-Pazopanib showed a significant reduction in tumor growth in a xenograft mouse model of thyroid cancer containing KRASG12R and BRAFV600E mutations (189). In an independent study, combining Carboplatin (CBDCA) and Radachlorin-photodynamic therapy (PDT) was shown to inhibit EGFR and PI3k activity while increasing PTEN activity. Treatment with these drug combinations resulted in significant tumor reduction due to activation of intrinsic apoptotic pathway (190). In a recent investigation, a combination of BRAF inhibitor (PLX4720) and Src tyrosine receptor/Bcr-Abl family inhibitor (Dasatinib) showed reduced tumor size, increased immune cell infiltration and apoptosis induction in an orthotopic ATC mouse model (191). Another study in which PPARγ ligand Troglitazone and the cholesterol-lowering drug Lovastatin were used to treat showed significant suppression of EGF-induced migration in ATC cells, with a concomitant reduction in Vimentin and N-cadherin (192). Dual inhibition of histone deacetylases and EGFR by CUDC-101 resulted in cell cycle arrest and reduction in metastatic properties, marked by increased expression of p21 and E-cadherin, and reduced expression of Survivin, XIAP, β-Catennin, N-Cadherin, and Vimentin. Also, CUDC-101 treatment of ATC tumors in mice caused significant tumor regression and prolonged survival (193). Synergistic cytotoxicity with Doxorubicin and Cucurbitacin B was observed in ATC cells in vitro, and this effect was mediated by B-cell chronic lymphocytic leukemia/lymphoma two family proteins, survivin, and reactive oxygen species and modulated by JNK2/STAT3 and ERK 1/2 (194). However, this effect is yet to be demonstrated in vivo.

In a separate study, a combination of HDAC inhibitor SAHA and the PARP inhibitor PJ34 exhibited synergistic effect against SW1736 cell growth in vitro. Further, this treatment also caused induction of TSHR but not of NISTTF1TTF2, and PAX8 mRNA levels. These data suggested that a combination of HDAC and PARP inhibitors may be used to target ATC cells (195). Similar synergistic effects were also observed when HDAC inhibitor PXD101 and HSP90 inhibitor NVP-AUY922 were used in ATC cells. This was concomitant with inactivation of PI3k/Akt signaling and activation of DNA damage response in ATC cells (196). Another HSP90 inhibitor, SNX5422 also revealed synergy with other HDAC inhibitors including PXD101, SAHA, and TSA (197). HDAC inhibitor/MKI and CUDC-101, showed a significant synergistic effect in ATC cells when combined with Carfilzomib, a second-generation proteasome inhibitor. The combination mainly affected cell cycle at G2/M phase followed by apoptosis marked by PARP cleavage and Caspase-3 activation (198).

It is important to note that not all combination treatments have shown synergy in ATC inhibition. Pan MEK inhibitor (U0126) and BRAF inhibitor (PLX4720) did not show any inhibition of invasion of ATC cells, in contrast to PTC cells; suggesting that migration and invasion in ATC cells are mediated by other non-MEK mechanisms (199). Hence, selection of a combination of drugs is crucial for improving the therapeutic efficacy. Strategic evaluation of combinations of drugs that are likely to be most effective will require genomic and proteomic analyses of the tumor.


ATC remains a clinical challenge because of its de-differentiated phenotype and highly aggressive features. Though the complex interplay of several signaling cascades in the process of ATC oncogenesis, metastasis, and chemoresistance is not clear.  Progression of DTCs to ATCs is caused, at least in part, by the accumulation of mutations in several critical signaling pathways including the Wnt, EMT, p53 and β-Catenin pathways. Several pre-clinical therapeutic studies including combinations of MKIs and HDACs inhibitors have shown encouraging results and this hold promise for investigation in clinical trials.  Less explored avenues in ATC research include the efficacy of histone methyltransferase and hTERT inhibitors. The role of hTERT in conferring genomic instability to ATC is well established and merits more comprehensive studies to explore efficacy in clinical management. Several clinical studies are ongoing to determine the safety and efficiency of novel drugs, but low patient accrual hinders these trials due to the rarity of ATC and limited long-term survival. Although targeting several pathways using MKIs has shown encouraging results, their optimal clinical utility is yet to be established. Combining several MKIs or using different salvage therapies might improve therapeutic outcomes. Further, evaluating drug treatment responses in primary cell cultures of patient’s tumors might help in guiding second line treatment.  An excellent case of such personalized therapy was demonstrated by Eckhard et al., wherein a patient’s tumor cells were cultured with Sorafenib, Vandetanib and MLN8054 (Aurora kinase inhibitor) in vitro while the patient was undergoing radiation and chemotherapy (Docetaxel and Cisplatin).  Based on the in vitro data, the patient was subsequently treated with Sorafenib and achieved 43-month disease free survival (200). Obtaining patient biopsies during treatment may help guide in understanding the mechanism of ATC progression and chemoresistance.

Additionally, the emergence of new genomic technologies might contribute to understanding the underlying tumor specific mutational landscape and in tailoring treatments. The existence of TAMs within ATCs hinders the capturing of ATC specific transcriptomic landscape via Next generation sequencing. Therefore deep sequencing and bioinformatics algorithms that account for TAMs might provide more meaningful data to understand the underlying genetic profile in ATC specimens. Undoubtedly, cellular, genomic, and molecular data are critical to developing better diagnostic and therapeutic approaches to this disease. However, clinical implications of personalized medicine need more comprehensive analysis of pharmacological markers to predict the course of treatment. Including such efforts in the management of ATC might help better manage this lethal malignancy.

Figure Legends:

Figure 1: Dysregulation of p53 pathway in ATC: Under non-stressful conditions, p53 is down-regulated by its negative regulators such MDM2, HMGA1, PIRH2 and COP1 which when bound with p53 cause its proteosomal ubiquitination. Upon DNA damage, due to extrinsic or intrinsic stress, p53 is activated by mediators such as ATM, ATR, and ARF resulting in its translocation into the nucleus, where it modulates transcriptional activity. p53 induces cell cycle arrest by activating p21 and GADD45, causes DNA repair by activating p48 and induces apoptosis by activating genes like Puma, Bax, DR5 and Fas. In ATC, loss-of-function mutations in TP53 and gain-of-function mutations in its negative regulators such as MDM2 and HMGA1 results in unchecked cell proliferation inspite of DNA damage. The function of p53 could be restored by using adenovirus mediated p53 expression in ATC cells, which has shown promising results in vitro.

Figure 2: Hyperactivation of MAPK pathway in ATC: Upon ligand binding, the receptor tyrosine kinases activates Ras which subsequently activates MAPKs (ERK/p38). The activated MAPKs translocate to the nucleus and cause cell proliferation, angiogenesis and metastasis by activating genes such as TGF-β1Vegfa and Tsp-1/Vimentin respectively. In ATC, several kinases including RTKs (EGFR, VEGFR, cMet, c-Myc), Ras (Kras), Raf (BRAFV600E) and ERK are hyperactivated due to gain-of-function point mutations, copy number gains or gene amplification. Hyperactivation of this pathway also causes indirect activation of PI3k/Akt and NF-κB pathways. Several specific or multi-kinase inhibitors (MKIs) which have shown anti-cancer effect in pre-clinical and clinical studies are shown.

Figure 3: PI3k/Akt pathway in ATC: PI3k/Akt pathway is highly activated in DTCs and the hyperactivation is sustained in ATC. Upon ligand-receptor interaction, PI3K is activated and converts PIP2 to PIP3. In turn this will lead to the activation of PDK-1 which phosphorylates Akt. Activated Akt (pAkt) can mediate its effects through several effector molecules such as mTOR (autophagy), GSK-3β (Wnt signaling activation), HIF1α (hypoxia induced angiogenesis), MMP-2 (cell migration and invasion), p21 (cell cycle) and Bad/Caspase-3, -9 (inhibition of apoptosis). Activating mutations are observed in P13KCA, Akt, and PDK-1 and Inactivating mutations are found in PTEN (negative regulator) in variable frequencies in ATC. Several inhibitors targeting different members of this pathway are shown.

Figure 4: Hyperactivated Wnt pathway in ATC: Wnt signaling operates during embryogenesis, wound healing and carcinogenesis, and control differentiation in the cells. During DTC to ATC transformation, this signaling is highly activated during this process. In the resting state, β-catenin is bound to the complex (Axin1, APC, GSK-3β and CK1) which prevents its translocation to the nucleus. However, When Wnt binds to the receptor, FRZ, DSH releases and binds to the complex leading to its dis-assembly.  As a result, β-catenin can freely translocate to the nucleus and activate genes such as Cyclin-D1 (cell cycle), c-MYC (angiogenesis), and several transcription factors involved in EMT. In ATC, activating mutations in CTNBB1 (β-catenin) and inactivating mutations in Axin1, GSK-3β,and APC have been observed. Dickkopf-1 is a Wnt antagonist and can be used to inhibit this signaling.

Figure 5: Role of NF-κB pathway in ATC: NF-κB signaling has diverse functions in immune as well as cancer cells. NF-κB exists in an inactive form in the cytosol, bound to its negative regulator, IκB. In ATC, upon CCL20 binding to its receptor (CCR6) IκK is actiated which phosphorylates  IκB and marks it for proteasomal degradation thus resulting in the release of NF-κB. Freed NF-κB translocates to the nucleus and cuase activation of several genes such as MMPs (involved in cellular migration), CXCR4 (Cell proliferation via paracrine signaling), c-IAP-1/2 (anti apoptotic genes) and TIMP-1. Quinacrine, an inhibitor for NF-κB, has shown significant inhibition of cell proliferation in vitro.

Table 1: Different categories of drugs used in preclinical and clinical studies in ATC

Chemotherapeutic agents
Topoisomerase inhibitor Doxorubicin, Etoposide
Microtubule assembly Paclitaxel, Vinorelbine, Docetaxel
DNA crosslinking agents Cisplatin, Carboplatin, Cyclophosphamide, Neoplatin
Nucleoside Analog Gemcitabine, 5- fluorouracil
Targeted inhibitors
ALK1 GSK461364A
Akt MK-2206 2HCL, Perifosine, GSK690693, GDC-0068, AT7867
Aurora Kinases MK-0457 (VX-680), SNS-314 mesylate, ZM447439, AZD1152 and MLN8054
Bcl2 Obatoclax
EGFR Cetuximab (C225), Manumycin A, Geldanamycin, Gefitinib (ZD1839)
HSP90 Tanespimycin (17-N-allylamino-17-demethoxygeldanamycin, NVP-A0Y922, SNX5422
I-κB Ciglitazone (upregulates TrailR1, -R2)
PARP Olaparib
PD-1 receptor Pembrolizumab
TGF-β LY2157299, SB 525334, LY2109761, Perfenidone, GW788388
SMO (Wnt signaling pathway) LDE225, LY2940680, PF-5274857, SANT-1
γ-secretase RO4929097, LY-411575
Anti-angiogenic agents
Vascular disrupting agent Combretastatin A4 phosphate (CA4P), Fosbretabulin
VEGF Bevacizumab, AZD2171, Cediranib
Multi-Kinase inhibitors
VEGF 1, 2 and 3, PDGFR and c-KIT Axitinib (AG-013736), Pazopanib
VEGFR1, 2 and 3, EGFR and RET kinases Vandetanib
VEGFR-1, PDGFR, RET, FLT-3 and CSF-1R Sunitinib
Bcr-Abl, PDGFR and c-kit Imatinib

and c-Kit

Sorafenib (Bay43-9006, Nexavar)
VEGFR-1, -2 and -3, PDGFRβ, RET, FGFR -1, -2, -3, -4 and c-KIT Lenvatinib (E7080)
VEGFR 2, RET, MET, kit Cabozantinib
VEGFR -1, -2, -3, RET, kit, PDGFR Motesanib
VEGFR -1, -3, PDGFR, FGFR1-3 Ninetedanib
RET, PDGFR, FGFR, FLT3, kit Ponatinib
MET, ALK, ROS1 Crizotinib
Epigenetic modifiers
HDAC inhibitors Valproic acid, Thailandepsin A (TDP-A), Trichostatin A (TSA), Suberoyl Amide Hydroxamic Acid (SAHA), N-hydroxy-7-(2-naphthylthio) heptanomide (HNHA)
BET inhibitors JQ1, I-BET762
HDACs, EGFR (dual inhibitor) CUDC-101
Proteosome inhibitors Carfilzomib, Bortezomib (PS-341)
PPARᵞ agonists Rosiglitazone, RS5444, Pioglitazone, Troglitazone


Table 2: Results from clinical trials of different drugs conducted between 2013-2016.

No. Drug Phase Cancer Number of patients Response Rate Progression free survival Overall survival Reference
1 Sorafenib (Bay43-9006, Nexavar) II ATC 20 PR in 2/20 (10%); Stable disease in 5/20 (25%) 1.9 months (201)
2 Carbozantinib III MTC 330 28% 11.2 (202)
3 Efatutazone 

+ Paclitaxel

I ATC 15 PR=1; 

SD= 7

3.3 months (139)
4 Pazopanib II Advanced and progressive medullary 35 5/35 9.4 19.9 (203)
5 Fosbretabulin + Paclitaxel/Carboplatin II ATC 8 20% 3.3 5.2 months (204)
6 Vemurafenib BRAFV600E positive, metastatic, radio-iodine refractory PTC 26 10/26 (204)
7 Axitinib II Advanced thyroid cancer 52 35% 16.1 23.2 (205)
8 Levatinib III Iodine refractor TC 261 64.8% 18.3 (206)
9 Sunitinib 

(second line of therapy)

II Progressive, radio-iodine 

Refractory thyroid cancer

25 5/20 (25%) 6 months 13 months (207)
10 Cabozantinib (XL-184) III Advanced MTC 11.2 months (208)


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[1] Abbreviations: ALK: Anaplastic Lymphoma Kinase; BET: Bromodomain and extra-terminal  containing protein; Cdk: Cyclin dependent kinase; EGFR: Epithelial Growth Factor Receptor; Fgfr: Fibroblast Growth Factor Receptor; FLT-3: FMS Related Tyrosine Kinase 3; Hsp90: Heat Shock Protein 90; Parp: Poly ADP ribose polymerase; PD-1: Programmed Cell Death Protein-1; PDGFR: Platelet-Derived Growth Factor Receptor; PPARᵞ: Peroxisome Proliferator-Activated Receptor gamma; VE-Cadherin; Vascular Endothelial Cadherin; VEGFR: Vascular Endothelial Growth Factor Receptor.

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