Advanced RAI-refractory thyroid cancer: an update on treatment perspectives

in Endocrine-Related Cancer
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  • 1 Endocrine Department, 401 General Military Hospital of Athens, Athens, Greece
  • | 2 Department of Clinical Therapeutics, Alexandra Hospital Athens University School of Medicine, Endocrine Unit, Athens, Greece
  • | 3 Endocrine Department, Evangelismos Athens General Hospital, Athens, Greece

Correspondence should be addressed to O Karapanou: olgakarapanou@yahoo.com
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During the last decades, the knowledge on follicular cell-derived thyroid cancer molecular biology has led to the evolution of a number of novel therapies for these tumors, mainly tyrosine kinase inhibitors. Lenvantinib, sorafenib and recently cabozantinib have been approved for differentiated thyroid cancer (DTC), while larotrectinib and entrectinib for neurotrophic-tropomyosin receptor kinase-fusion thyroid cancer. For radioiodine (RAI) refractory DTCs ongoing research aims to identify agents that may restore RAI-avidity via redifferentiation protocols (vemurafenib or dabrafenib and trametinib) or combination treatments. These treatments are based on the tumor molecular signature. The treatment with targeted therapies has changed the therapeutic strategies and the disease prognosis, however drug resistance remains the main reason for treatment failure. Thus, the understanding of both molecular pathways implicated in tumorigenesis, and tumoral escape mechanisms, are of paramount significance for the development of new therapies for DTC. The present review focuses on the molecular landscape of DTC, the approved targeted therapies as well as the mechanisms of drug resistance. Furthermore, it points to the ongoing research and the future perspectives for the development of more efficient drugs for DTC.

Abstract

During the last decades, the knowledge on follicular cell-derived thyroid cancer molecular biology has led to the evolution of a number of novel therapies for these tumors, mainly tyrosine kinase inhibitors. Lenvantinib, sorafenib and recently cabozantinib have been approved for differentiated thyroid cancer (DTC), while larotrectinib and entrectinib for neurotrophic-tropomyosin receptor kinase-fusion thyroid cancer. For radioiodine (RAI) refractory DTCs ongoing research aims to identify agents that may restore RAI-avidity via redifferentiation protocols (vemurafenib or dabrafenib and trametinib) or combination treatments. These treatments are based on the tumor molecular signature. The treatment with targeted therapies has changed the therapeutic strategies and the disease prognosis, however drug resistance remains the main reason for treatment failure. Thus, the understanding of both molecular pathways implicated in tumorigenesis, and tumoral escape mechanisms, are of paramount significance for the development of new therapies for DTC. The present review focuses on the molecular landscape of DTC, the approved targeted therapies as well as the mechanisms of drug resistance. Furthermore, it points to the ongoing research and the future perspectives for the development of more efficient drugs for DTC.

Introduction

During the last decades, the knowledge on differentiated thyroid cancer (DTC) molecular biology has evolved. Novel therapies for thyroid cancer (TC) are tyrosine kinase inhibitors (TKIs). Lenvatinib, sorafenib and recently cabozantinib have been approved for DTC. The treatment with these agents has changed the therapeutic strategies and the disease prognosis. However, as drug resistance may occur, the understanding of the molecular pathways implicated in tumorigenesis is of paramount importance.

The main intracellular signaling pathways involved in the process of tumorigenesis in TC are the mitogen-activated protein kinase (MAPK) and the phosphatidylinositol-3 kinase (PI3K) pathway. Mutations of tyrosine kinase (TK) receptors or other factors involved in these pathways may lead to constant activation of the pathway leading to uncontrolled cellular proliferation, decreased cell apoptosis, cellular dedifferentiation, migration and increased tumor angiogenesis (Preteet al.2020). Not only common genetic modifications but also epigenetic alterations may underlie the spectrum of biological behavior of these neoplasms (Asa & Ezzat 2018). The main targets of molecular alterations that have been implicated in the tumorigenesis of TC include BRAF, RAS, PTEN, TERT, AKT, PIK3CA,as well as RET and NTRKfusions (Cancer Genome Atlas Research 2014). RET/PTC rearrangements are usually found in PTC patients diagnosed after exposure to radiation at a young age for medical reasons or after nuclear accidents. The acquisition of further activating mutations in other genes or loss of function mutations in tumor suppressor genes ex TP53is a frequent event in advanced thyroid cancer leading to dedifferentiation (Fagin & Wells 2016).

In this review, we describe the evolution of novel targeted therapies based on the molecular pathogenesis of tumorigenesis, the possible mechanisms for drug resistance to these agents as well as future perspectives.

Differentiated thyroid cancer

The usual treatment for thyroid cancer includes surgery and administration of radioactive iodine (RAI). The purpose of this treatment is to destroy any normal thyroid remnants but also to act as an adjuvant therapy in case micrometastases have occurred prior to removal of the tumor. The efficacy of RAI to perform this action depends on the degree of differentiation of the cancer cells. Out of DTC patients up to 5–10%, that is 6–7 new cases/year/million develop metastatic disease, mostly located in lungs and bones. Two-thirds of these tumors (4–5 new cases/year/million) lose their capacity to uptake radioiodine because of dedifferentiation and become radioiodine refractory (RAI-R); their 10-year survival rate is then reduced to less than 20%. Older age, large metastases, poorly differentiated thyroid tumors and high FDG uptake (Duranteet al.2006) have been identified as markers for RAI resistance. According to the recent ETA guidelines (Fugazzolaet al.2019), the proposed criteria to define RAI refractory disease are the following: (i) absence of RAI uptake in all lesions on scintigraphy; (ii) absence of RAI uptake in some but not in all lesions; (iii) progression despite RAI uptake; (iv) having reached the maximum recommended RAI activity. The most recently published recommendations by the American and European Thyroid and Nuclear Medicine Societies combined define RAI refractoriness as (i) no 131I uptake on a diagnostic 131I scan; (ii) no 131I uptake on a 131I scan performed several days after 131I therapy; (iii) 131I uptake is present in some but not other tumor foci; (iv) DTC metastasis(es) progress despite 131I uptake; (v) DTC metastasis(es) progress despite a cumulative 131I activity of >22.2 GBq (600 mCi) (Tuttleet al.2019). This statement also stresses the fact that the criteria will continue to evolve as diagnostic and therapeutic tools are developed.

Dedifferentiation mechanism

The normal uptake of iodine by the thyroid cell involves the following steps: thyroid-stimulating hormone (TSH) couples to its receptor (TSH-R) and through the cAMP pathway induces binding of thyroid-specific transcription factor paired-box 8 (PAX8) to the sodium iodide symporter (NIS) gene promoter and thus upregulates its transcription. Under TSH stimulation, NIS molecules actively transport iodide from the blood into thyroid cells in the basal membrane, followed by transportation through pendrin in the apical membrane of the cell into the follicular lumen; thereafter, under the thyroid peroxidase (TPO) activity, iodide is oxidized and organified on the thyroglobulin (Tg) tyrosine residues for the formation of thyroid hormones (Kogai & Brent 2012). The expression of these iodide-handling genes, especially NIS and TPO,is frequently decreased in thyroid cancer (Kogai & Brent 2012) (Fig. 1). Reduced NIS expression results in loss of the ability of thyroid cancer cells to concentrate RAI, while reduced TPO expression results in decreased oxidation of RAI limiting its effective half-life (Remyet al.2008). Since the 131I effective radiation dose depends on total uptake and its effective half-life, impaired iodide metabolism in thyroid cancer cells could explain radioiodine treatment failure and the consequent unfavorable clinical outcome. Another issue hampering RAI efficacy in metastatic sites is that, in general, the radiation dose delivered to extrathyroidal tissues is 1000–10,000 times lower than that delivered to the thyroid gland (Kogai & Brent 2012).

Figure 1
Figure 1

Altered expression of iodide-handling genes in thyroid cancer: Under TSH stimulation, the sodium iodide symporter NIS, encoded by SLC5A5,actively accumulates iodide through the baso-lateral pole into the thyrocyte. Iodide is transported transcellularly to the apical membrane of the thyrocyte where pendrin, encoded by SLC26A2,mediates apical iodide efflux to the follicular lumen. At the apical pole of the thyrocytes iodide is oxidated and incorporated into tyrosyl residues of the Tg molecule to form MIT and DIT. This oxidation process is catalyzed by the enzyme TPO in the presence of H2O2 generated by DUOX2. A second TPO-catalyzed oxidation process is the coupling of two iodotyrosines inside the Tg molecule to form hormonally active iodothyronine, T3 and T4 which are secreted into the bloodstream. The downregulated factors encoded by relevant genes in DTC are marked with a gray arrow. DIT, di-iodotyrosine; DTC, differentiated thyroid cancer; DUOX2, dual oxidase maturation factor 2; MIT, mono- iodotyrosine; NIS, sodium iodide symporter; Tg, thyroglobulin; TPO, thyroperoxidase; TSH, thyroid-stimulating hormone; T3, triiodothyronine; T4, thyroxine.

Citation: Endocrine-Related Cancer 29, 5; 10.1530/ERC-22-0006

Molecular landscape of DTC and altered signaling pathways

Important information about the genetic alterations in papillary thyroid carcinomas (PTCs) has been obtained from the study of the genetic landscape of a large series of PTCs. This information was published as the ‘Genetic Atlas of papillary thyroid cancer’ (Cancer Genome Atlas Research 2014). From this and other studies, the vast majority of genetic alterations in DTC have been identified: point mutations (BRAF, N-,H-,K-RAS, EIF1AX, TERT and PIK3CA) account for 75%, followed by gene fusions (RET/PTC,PPARγ/PAX8, NTRK1/3and ALK) which account for 15%; copy number alterations (22 q being the most frequent) are less common (Cancer Genome Atlas Research 2014). The different DTC histological types harbor distinct mutation profile, signaling pathways and clinical course (Cancer Genome Atlas Research 2014).

BRAF and RAS point mutations as well as RET/PTC and NTRK1rearrangements are found in more than 70% of PTCs and result in upregulation of the MAPK signaling pathway (Cancer Genome Atlas Research 2014). On the other hand, follicular thyroid carcinoma and follicular variant PTC harbor mutually exclusive RAS mutations or PPARγ/PAX8 genetic rearrangements (Nikiforovaet al.2003). Thus, based on genotype-phenotype correlation, DTCs are classified as either ‘BRAF-like’ or ‘RAS-like’ (Cancer Genome Atlas Research 2014), the former characterized by downregulated and the latter by preserved expression of thyroid differentiation genes.

BRAFV600E mutation, the most frequently found in PTCs (up to 60%), is the most potent driver of the MAPK-pathway (Lito et al. 2012). The higher the MAPK-pathway output the lower the expression of genes involved in iodide metabolism and in particular NIS (Chakravarty et al. 2011). In addition to decreased expression, BRAFV600E expression may also cause mislocation of NIS into the cytoplasm in thyroid cells (Riesco-Eizaguirre et al. 2006). Thus, BRAF V600E point mutation is inversely correlated to thyroid differentiation score (Cancer Genome Atlas Research 2014, Nagarajahet al.2016).

Further genetic alterations involving the PI3K/AKT signaling pathway may occur in advanced and dedifferentiating tumors. MAPK and PIK3CA cascades are overlapping: RASand RET/PTC genetic alterations are not only the major MAPK drivers but also cross-activate PIK3CA downstream. Additional mutations involving TP53, AKT1 and CTNNB1 genes are identified in poorly differentiated and anaplastic carcinomas (Kondoet al.2006). It is well described that the accumulation of such additional mutations in PTCs leads to further tumor dedifferentiation (Fagin & Wells 2016, Giordano 2018, Pozdeyevet al.2018). Genetic alterations inducing follicular cell-derived thyroid cancer dedifferentiation are depicted in Fig. 2.

Figure 2
Figure 2

Genetic alterations inducing follicular cell-derived thyroid cancer dedifferentiation. Activating point mutations/fusions/gene amplifications are indicated in BOLD font. Loss-of-function mutation/copy number losses are shown in regular font. ATC, anaplastic thyroid carcinoma; FTC, follicular thyroid carcinoma; HCTC, hürthle cell thyroid carcinoma; PTC, papillary thyroid carcinoma.

Citation: Endocrine-Related Cancer 29, 5; 10.1530/ERC-22-0006

Apart from genetic pathways, epigenetic mechanisms may be implicated in TC pathogenesis. It has been shown that BRAFV600E may also downregulate NIS expression through epigenetic mechanisms involving histone acetylation and DNA methylation (Zhanget al.2014) leading to chromatin remodeling, prevention of transcription factors’ binding (Dhall & Chatterjee 2011) and consequently to NIS silencing (Zhanget al.2014). Direct methylation of iodide-metabolizing genes such as NIS and TSH-R gene is usually associated with gene silencing. In this way, aberrant methylation of NIS promoter contributes to loss of iodide uptake, that is RAI resistance (Xing 2007). It has been demonstrated that iodide uptake in dedifferentiated thyroid tumors is related to NIS gene methylation status (Venkataramanet al.1999). Finally, it is well-known that DNA-methyltransferases interact with histone deacetylase (HDCA) (Wadeet al.1999, Robertson 2002) and HDCAs are recruited by methyl-CpG-binding protein (Nanet al.1998, Wadeet al.1999). Thus, both epigenetic mechanisms coordinate for the regulation of gene expression.

RAI-R DTC current therapy and future perspectives

The treatment of dedifferentiated, RAI refractory DTC is challenging. Based on the knowledge of TC molecular pathology, scientists attempted to redifferentiate thyroid cancer cells in order to restore NIS expression and consequently RAI-avidity by targeting central mediators of the MAPK signaling pathway. In 2013, Ho et al. conducted a study to investigate whether the MAPK kinase (MEK) 1 and MEK 2 inhibitor selumetinib could restore the response to radioiodine in patients with metastatic thyroid cancer (Hoet al.2013). Dosimetry with iodine-124 positron-emission tomography (PET) was performed before and 4 weeks after treatment with selumetinib (75 mg twice daily). Twenty patients were evaluable for the outcome; in all RAS-mutant patients the dosimetric threshold was exceeded and they were all treated with radioiodine. By contrast, four out of nine BRAF-mutant patients increased RAI uptake but only one reached the prespecified dosimetry threshold appropriate to receive a therapeutic RAI activity. The international phase III ASTRA study demonstrated that adding selumetinib to postoperative RAI did not improve the complete remission rate (CRR) in high-risk nonmetastatic thyroid cancer patients. The CRR was similar among patients with or without BRAF/NRAS mutations (Wirth 2019). Thereafter, another study was undertaken using a similar dosimetry protocol and a selective BRAF inhibitor, dabrafenib. Six out of 10 BRAFV600E-mutant patients acquired new RAI uptake and were delivered a therapeutic activity resulting in clinical benefit; two patients with partial response and four with stable disease (Rothenberg et al. 2015). Outcomes were similar when another selective BRAF inhibitor vemurafenib was used to enhance lesional iodide uptake in RAI refractory BRAF mutant thyroid cancer patients; six out of ten patients responded on vemurafenib having partial responses 6 months post-RAI administration (Dunnet al.2019).

The complexity of biological pathways implicated in thyroid cancer has promoted the design of drugs targeting specific pathways; subsequently, clinical trials have been initiated using these targeted therapies. TKIs have been used due to their property to dephosphorylate intracellular proteins of the MAPK signaling pathway (Cancer Genome Atlas Research 2014); they also target alternative activators of the pathway such as the EGF receptor (EGFR), the vascular endothelial growth factor receptor (VEGFR), fibroblast growth factor receptor (FGFR) and hepatocyte growth factor receptor encoded by the cMET proto-oncogene (Bottaro et al. 1991). Among several multi-TKIs clinical trials (Cabanillas et al. 2019) two (sorafenib and lenvatinib) have been FDA and EMA approved for the treatment of advanced RAI-refractory thyroid cancer based on the results of two pivotal phase three clinical trials DECISION and SELECT respectively (Brose et al. 2014, Schlumberger et al. 2015). Lenvatinib has an overall survival benefit compared to sorafenib (ORR 64.8% for lenvatinib vs 12% for sorafenib and progression-free survival 18.3 months for lenvatinib vs 10.8 months for sorafenib) due to its potency for FGFR-1 inhibition compared to sorafenib; the FGFR pathway has been associated with resistance to VEGF/VEGFR inhibitors (Grande et al. 2012). Lenvatinib has an additional inhibitory effect on the tumor microenvironment through blocking FGFR and PDGFβ. Major treatment-related adverse events were hand-foot skin reaction for sorafenib and hypertension for lenvatinib (Broseet al.2014, Schlumbergeret al.2015). Based on the results of SELECT study, lenvatinib is the first treatment option with 64.8% ORR. Of note, a SELECT subanalysis demonstrated higher ORR (72% vs 55%) and less toxicity in younger (<65 years) vs older patients (>65 years). It is of note that, OS was significantly improved among patients age >65 years, compared with placebo (Brose et al. 2017).

In September 2021, Food and Drug Administration (FDA) approved cabozantinib, a RET, VEGFR2, c-MET and KIT inhibitor following the results of COSMIC-311 clinical trial (NCT03690388). In this global phase 3 trial, 258 patients were randomly assigned to cabozantinib orally (60 mg once daily) or matching placebo; the median PFS was 11.0 months (95% CI: 7.4, 13.8) in the cabozantinib arm compared to 1.9 months (95% CI 1.9, 3.7) for those receiving placebo. The objective response rate (ORR) was 18% (95% CI: 10%, 29%) and 0% (95% CI 0%, 11%) in the cabozantinib and placebo arms respectively (Broseet al.2021). Most frequent grades 3 and 4 adverse events under cabozantib were palmar-plantar erythrodysesthesia, hypertension and fatigue. Documented adverse events for sorafenib, lenvatinib and cabozantib during DECISION, SELECT and COSMIC-311 clinical trials, respectively, are depicted in Table 1.

Table 1

Documented adverse events for sorafenib, lenvatinib and cabozantinib during DECISION, SELECT and COSMIC-311 clinical trials.

AEs (%) (all grade)SORAFENIBLENVATINIBCABOZANTINIB
Hand–foot skin reaction76.331.835
Diarrhoea68.659.444
Alopecia6711.1
Rash/desquamation50.216.1
Fatigue49.85919
Weight loss46.946.418
Hypertension40.667.819
Anorexia31.950.220
Dyspepsia10
Oral mucositis (functional/symptomatic)23.235.611
Dysgeusia16.93
Dry mouth13.89
Pruritus21.33
Nausea20.84121
Headache17.927.68
Cough15.55
Constipation1514.610
Dyspnea14.512
Neuropathy: sensory14.5
Abdominal pain - not otherwise specified1411.56
Pain, extremity – limb13.56
Arthralgia187
Myalgia14.62
Peripheral edema11.1
Dermatology - Other13
Hair color changes3
Voice changes12.12410
Fever11.1
Vomiting11.128.414
Back pain10.65
Pain, other10.64
Pain, throat/pharynx/larynx10.1102
Dehydration1
Insomnia3
Pulmonary embolism2.72
Haemoptysis1
Deep vein thrombosis2
Pleural effusion1
Pneumonia2
Gastro-oesophageal reflux disease1
Spinal fracture1
Confusional state3
Laboratory
 Serum TSH increase33.3
 Hypocalcaemia18.86.916
 Hypomagnesaemia11
 ALT increase12.623
 AST increase11.123
 Gamma-glutamyltransferase increase3
 Alkaline phosphatase increase7
 Hypokalemia7
 Hyponatremia2
 Amylase increase3
 Anaemia4
 Neutropenia3
 Leukopenia4
 Neutrophil count decrease4
 Electrolyte imbalance1
 Proteinuria3114

It is advised that active surveillance should be considered for patients with slow rate disease progression. Finally, in patients previously treated either lenvatinib or sorafenib having aggressive disease and no available standard of care cabozantinib significantly prolonged progression-free survival and currently is an alternative treatment option (Broseet al.2021).

For those patients not responding to the abovementioned and approved TKIs or those not tolerating treatment-related adverse events, novel targeted therapies have been used based on the tumor’s molecular signature. It has recently been elucidated that 2.2% of BRAF-WT aggressive PTCs associated with younger age and more aggressive disease at presentation, carry a translocation of ALK with echinoderm microtubule associated-protein 4 (ALK-EML4 fusion) ALK-EML4 and several other ALK translocations have been identified in RAI-R DTCs (Demeureet al.2014). It has been demonstrated (Godbertet al.2015) that these patients might benefit from crizotinib antitumoral effect. Another oncogenic event in thyroid cancer is a rearrangement involving one of the neurotrophic-tropomyosin receptor kinase (NTRK) family including three genes NTRK1, NTRK2and NTRK3. NTRK fusions are approximately eight times more common in children than in adults; the frequency ranges between 18.3 and 25.9% in children (Prasadet al.2016, Pekovaet al.2020) compared to 2.3–3.4% in adults (Leeet al.2020, Solomonet al.2020). For TRK-positive thyroid cancers, two highly selective TRK inhibitors have been approved; larotrectinib and entrectinib. In phase 1, 2 trial including children, adolescents and adults larotrectinib proved to be a highly potent (75% objective response rate) and durable therapy for tumors harboring TPK-fusions (Drilonet al.2018). The other TRK inhibitor, entrectinib, also targets ALK and ROS1 TKs. Its efficacy and safety profile have been documented through the ALKA-372–001 and STARTRK-1 phase 1 trial (Drilonet al.2017) and the ongoing STARTRK-2 phase 2 trial (NCT02568267); the overall objective response rate (mostly partial response) in these studies was 57% (95% CI 43.2, 70.8) (Doebeleet al.2020). Finally, following dataset analysis of LIBRETTO-001 trial (NCT03157128) on May 2020 selpercatinib was FDA approved for RET-fusion positive thyroid; ORR was 79% (95% CI 54, 94) and 1-year PFS 64% (95% CI 54, 94) (Subbiahet al.2018, Wirthet al.2020). In December 2020, another selective RET-inhibitor praseltinib for RET-fusion positive RAI-refractory thyroid cancer patients. Its efficacy was documented in ARROW multi-cohort clinical trial (NCT03037385); for the subgroup of thyroid cancer patients harboring RET fusions ORR was 89% (95% CI 52, 100); all responding patients had responses lasting 6 months or longer (Subbiahet al.2021).

Future perspectives aim to restore RAI-avidity via redifferentiation protocols. The first prospective phase 2 clinical trial assessed vemurafenib, a selective BRAF inhibitor in patients with RAI-refractory PTC harboring BRAF-V600E mutation; vemurafenib showed antitumor activity in both naïve (best overall response of partial response in 10 of 26 patients) and in previously treated with a multikinase inhibitor (best overall response of partial response in 6 of 22 patients) patients (Broseet al.2016). Iravani et al. reported promising results using combined MEK- and BRAF inhibition (trametinib & dabrafenib respectively) under concurrent thyroid hormone withdrawal (Iravaniet al.2019). One out of three NRAS-mutant and all three BRAF-V600E-mutant patients restored RAI uptake and were rendered suitable for RAI therapy. Jaber et al. reported similar results (Jaberet al.2018). Based on these results the largest redifferentiation non-randomized clinical trial was started and is ongoing using combined dabrafenib and trametinib followed by RAI for the treatment of refractory metastatic DTC (NCT03244956). Approved TKIs and large on-going clinical trials for RAI-refractory advanced DTC are depicted in Tables 2 and 3, respectively.

Table 2

Approved TKIs for RAI-refractory advanced DTC.

TKIsTargetsFDA/EMA approvedClinical trials
SorafenibVEGFR1-3, PDGFβ, RET, RET/PTC, BRAF, c-KITYES(RAI-R PTC)NCT00984282 (DECISION)
LenvatinibVEGFR1-3, PDGFβ, RET, FGFR-IYES(RAI-R PTC)NCT01321554 (SELECT)
CabozantinibTie-2, c-MET, KIT, VEGFR1, VEGFR2, RETFDA YES(RAI-R PTC)

EMA NO
NCT03690388 (COSMIC-311)
EntrectinibNTRK1/2/3, ROS1, ALKYES (NTRK+)NCT02097810 (STARTRK-1)

NCT02568267 (STARTRK-2 )
LarotrectinibNTRK1/2/3YES (NTRK+)NCT02122913 (LOXO-TRK-14001)

NCT02637687 (SCOUT)

NCT02576431 (NAVIGATE)
SelpercatinibRETYES (second-line treatment)NCT03157128 (LIBRETTO-001)
PralsetinibRETFDA YES

EMA NO
NCT03037385 (ARROW)
Table 3

Promising drugs for RAI-refractory advanced DTC.

TKIsMechanism/targetsClinical trialsPhase/status
Lenvatinib + DenosumabVEGFR1-3, PDGFβ, RET, FGFR-I + RANKL (Bone metastases from RAI-refractory DTC)NCT03732495 (LENVOS)2 (active, recruiting)
Cyclophosphamide + SirolimusmTORNCT030993562 (active, recruiting)
Durvalumab + TremelimumabPD-L1 + CTLA-4NCT03753919 (DUTHY)2 (active, recruiting)
TPX-0046RET/SRC (RET fusion DTC)NCT041613911/2 (active, recruiting)
ImatinibPDGFRα (restore NIS function and RAI sesnsitivity)NCT034690111 (active, recruiting)
Dabrafenib + TrametinibBRAFV600E,K601E + N,H,KRASNCT03244956 (MERAIODE)2 (active, not recruiting)
Dabrafenib + LapatinibBRAF V600E, K601E + EGFR, HERNCT019470231 (active, not recruiting)
ApatinibVEGFR2NCT030488773 (active, not recruiting)
VandetanibVEGFR2, VEGFR3, EGFR, RETNCT01876784 (VERIFY)3 (active, not recruiting)
Lenvatinib + PembrolizumabVEGFR1-3, PDGFβ, RET, FGFR-I + PD-L1, L2NCT029739972 (active, not recruiting)
CrizotinibALKNCT011215881 (active, not recruiting)

Notably, epigenetic mechanisms have also been targeted for possible therapy. Thus, an in vitro study showed induction of the NIS protein expression in the cell membrane and radioiodine uptake in thyroid cancer cells by simultaneously suppressing the MAPK and PI3K/AKT pathways and histone deacetylase (HDAC) (Houet al.2010). These preliminary data provide evidence for novel therapeutic strategies aiming to restore radioiodine avidity in thyroid cancers targeting the deacetylation-induced NIS downregulation with specific HDAC inhibitors whose effect could be amplified when combined with MAPK or PI3K/AKT/mTOR inhibitors in thyroid cancer cells (Houet al.2010).

Finally, the immune landscape of BRAFV600E-mutant PTCs has been unraveled showing high levels of programmed death-ligand 1 (PD-L1), human leukocyte antigen G and macrophage components compared to BRAF WT tumors. As tumor cells are known to interact with the immune system cells, immune checkpoint inhibitor PD-L1 was tested in patients with advanced PD-L1-positive papillary or follicular thyroid cancer; however, ORR was as low as 9% (Mehnertet al.2019). The most prominent explanation is that DTC harbors low mutational burden and induces low immunogenicity. Under these circumstances, immunotherapy can only serve as an add-on treatment with TKIs. A clinical IB/II trial using a combination of lenvatinib with pembrolizumab is ongoing (NCT02973997).

Possible mechanisms of drug resistance

Various tumoral escape mechanisms have been proposed. Azouzi and Schlumberger focused on the role of reactive oxygen species (ROS)-generating NADPH oxidase (NOX4) which is increased in PTC (Azouziet al.2017). Their study revealed that BRAF-V600E upregulates NOX4 expression via the TGFB/SMAD3 signaling pathway in thyroid cancer cells (Azouziet al.2017). NOX4-ROS production represses NIS expression by impairing the binding of thyroid-specific transcription factor paired-box gene 8 (PAX8) to the NIS gene promoter in follicular cells. The authors pointed out that NOX4 could serve as a potential therapeutic target along with other MAPK-kinase inhibitors aiming to potentiate their effect on RAI-refractory DTC redifferentiation.

Another tumoral escape mechanism that has been suggested is rebound overexpression of HER2/3 that activates the mTOR cascade as well as MAPK. This was identified in a study where the selective BRAF inhibitor vemurafenib targeted RAI-refractory BRAF mutant tumors. Thus, the application of a Her2/3 inhibitor could lead to a new therapeutic strategy for a number of patients with progressive thyroid cancer (Kremseret al.2003). Based on the findings of Cheng et al. (2017), where combined therapy using Her 3 inhibitor lapatinib and BRAF/MEK inhibitor resulted in a more significant redifferentiation effect compared to BRAF/MEK inhibition alone, a phase I combination study (dabrafenib–lapatinib) was initiated in patients with BRAFV600E RAI-refractory DTC and is ongoing (NCT01947023). The major signaling pathways involved in DTC are depicted in Fig. 3.

Figure 3
Figure 3

Major signaling pathways for follicular thyroid cancer.

Citation: Endocrine-Related Cancer 29, 5; 10.1530/ERC-22-0006

Next-generation TRK inhibitors, such as selitrectinib, repotrectinib and taletrectinib, are evolving on ongoing clinical trials to overcome mechanisms of acquired drug resistance including NTRK kinase domain mutations, ‘solvent front’ mutations causing direct steric hindrance by limiting drug accessibility to the kinase ATP-binding pocket or upregulation of bypass signaling pathways (Haradaet al.2021, Murrayet al.2021). Promising drugs and their mechanism are summarized in Table 3.

Conclusion

When advanced thyroid cancer becomes refractory to RAI treatment, the therapeutic options include locoregional treatments (external radiation, radiofrequency ablation, cryoablation and embolization) and administration of multi-TKIs targeting the MAPK signaling pathway. Of the two FDA-approved TKIs, sorafenib and lenvatinib, the latter appears to be more potent due to inhibition of FGFR and PDGFβ that act as alternative activators of the pathway. Cabozantinib is a second-line treatment option in patients unresponsive to sorafenib or lenvatinib based on the results of COSMIC-311 study. Genetic and epigenetic tumoral escape mechanisms have been identified. Thus, future research aims to explore ways to restore RAI-avidity via redifferentiation protocols (vemurafenib or dabrafenib and trametinib) or combination treatments based on the tumor molecular signature. Thus, novel treatments may offer in the near future additional therapeutic tools for these cases.

The timing of the initiation of therapy with these agents is of paramount importance. The decision for treatment with these factors should be based on the knowledge that a delay may be a risk of further dedifferentiation of the tumor and ultimately a lower efficacy of the drugs. However, it should be mentioned that the majority of patients with RAI refractory DTCs may show a slow rate of disease progression. Finally, the decision for therapeutic intervention should be balanced between the benefits and risks of such treatments.

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of this review.

Funding

This work did not receive any specific grant from any funding agency in the public, commercial, or not-for-profit sector.

Author contribution statement

O K and G S drafted the manuscript. B V, M A and K S edited and critically revised the manuscript.

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    Altered expression of iodide-handling genes in thyroid cancer: Under TSH stimulation, the sodium iodide symporter NIS, encoded by SLC5A5,actively accumulates iodide through the baso-lateral pole into the thyrocyte. Iodide is transported transcellularly to the apical membrane of the thyrocyte where pendrin, encoded by SLC26A2,mediates apical iodide efflux to the follicular lumen. At the apical pole of the thyrocytes iodide is oxidated and incorporated into tyrosyl residues of the Tg molecule to form MIT and DIT. This oxidation process is catalyzed by the enzyme TPO in the presence of H2O2 generated by DUOX2. A second TPO-catalyzed oxidation process is the coupling of two iodotyrosines inside the Tg molecule to form hormonally active iodothyronine, T3 and T4 which are secreted into the bloodstream. The downregulated factors encoded by relevant genes in DTC are marked with a gray arrow. DIT, di-iodotyrosine; DTC, differentiated thyroid cancer; DUOX2, dual oxidase maturation factor 2; MIT, mono- iodotyrosine; NIS, sodium iodide symporter; Tg, thyroglobulin; TPO, thyroperoxidase; TSH, thyroid-stimulating hormone; T3, triiodothyronine; T4, thyroxine.

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    Genetic alterations inducing follicular cell-derived thyroid cancer dedifferentiation. Activating point mutations/fusions/gene amplifications are indicated in BOLD font. Loss-of-function mutation/copy number losses are shown in regular font. ATC, anaplastic thyroid carcinoma; FTC, follicular thyroid carcinoma; HCTC, hürthle cell thyroid carcinoma; PTC, papillary thyroid carcinoma.

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    Major signaling pathways for follicular thyroid cancer.

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    • Export Citation
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