The Molecular Basis for Radioiodine Therapy

Abstract

Radioactive iodine (radioiodine) therapy is a standard and effective therapeutic approach for high-risk differentiated thyroid carcinomas, based on the unique ability of the thyroid follicular cell to accumulate iodide through the sodium/iodide symporter (NIS). However, a recurrent limitation of radioiodine therapy is the development of radioiodine-refractory differentiated thyroid carcinomas, which are associated with a worse prognosis. Loss of radioiodine accumulation in thyroid carcinomas has been attributed to cell dedifferentiation, resulting in reduced NIS expression and NIS intracellular retention involving transcriptional and posttranscriptional or posttranslational mechanisms, respectively. Emerging therapies targeting the oncogene-activated signal pathways potentially involved in thyroid carcinogenesis have been able to recover radioiodine accumulation in radioiodine-refractory tumors, which constitutes the rationale of redifferentiation therapies. Here, we will comprehensively discuss the molecular mechanisms underlying radioiodine therapy, refractoriness to radioiodine therapy in differentiated thyroid carcinomas, and novel strategies for restoring radioiodine accumulation in radioiodine-refractory thyroid carcinomas.

1. Introduction

The ability of the thyroid follicular cell to accumulate iodide constitutes the cornerstone for diagnostic scintigraphy and therapy for hyperfunctioning thyroid tissue, as well as for differentiated thyroid carcinoma and their metastases after thyroidectomy [1]. Radioactive iodine (radioiodine) administration used in thyroid tissue remnant ablation after thyroidectomy and adjuvant therapy in metastatic differentiated thyroid carcinomas has been possibly the most successful internal radiation therapy ever designed. In patients with high-risk differentiated thyroid carcinomas, retrospective studies have demonstrated that the ability of tumor cells to accumulate radioiodine is the best indicator of disease-free and of overall survival [2].

Currently, thyroid hormone withdrawal and recombinant thyrotropin-stimulated radioiodine adjuvant therapy are considered in intermediate-risk carcinomas and are routinely recommended for high-risk differentiated thyroid carcinomas after total thyroidectomy [3]. However, differentiated thyroid tumors often exhibit reduced (or even undetectable) radioiodine accumulation, compared with normal thyroid tissue, and are diagnosed as cold nodules using thyroid scintigraphy. Despite this reduction, over 70% of differentiated thyroid carcinomas accumulate radioiodine to some extent, which is still sufficient to achieve adequate radioiodine accumulation for treatment. Unfortunately, 30% of metastatic differentiated thyroid tumors completely lose their ability to accumulate iodide, with this percentage increasing up to 70% when the oncogene BRAFV600E is present. This causes thyroid tumors to become refractory to radioiodine therapy and is associated with a poor outcome. Patients with thyroid cancer metastases that accumulate iodide show a survival rate at 10 years of ~60%, while survival is drastically reduced to ~10% in patients with radioiodine refractory metastases [4]. Therefore, a better understanding of the biological mechanisms leading to differentiated thyroid carcinoma resistance to radioiodine therapy will certainly have major implications for its treatment [5].

The clinical experience of radioiodine theranostic in the management of differentiated thyroid cancer has opened up a complete new field related to developing strategies to extend this promising approach to non-thyroidal cancers. Although, in addition to thyroid cancer, functional endogenous radioiodine accumulation has only been observed in breast and ovarian cancer [6, 7], this could be key for radioiodine being used as an effective therapeutic tool. The ectopic induction of radioiodine accumulation using gene transfer has paved the way for the development of new therapeutic strategies to treat tumors with radioiodine, as in differentiated thyroid cancer. Since a pioneering study successfully induced iodide accumulation in malignant transformed thyroid cells that did not accumulate iodide, thereby rendering them sensitive to radioiodine treatment [8], a large body of evidence has shown the feasibility of inducing radioiodine accumulation in several cancer cell lines [9, 10].

2. Iodide metabolism in the thyroid follicular cell

Iodine is an essential constituent of thyroid hormones. Therefore, a fundamental condition for normal thyroid hormonogenesis is that iodide—an extremely scarce environmental micronutrient—should be made available in sufficient amounts to the thyroid follicular cells (also known as thyrocytes), which have developed a remarkably efficient and specialized iodide-handling system. Under physiological conditions, the thyroid gland accumulates iodide al concentrations up to 40 times those in the plasma. The sodium/iodide symporter (NIS) is the key plasma membrane glycoprotein, which is located at the basolateral surface of the thyroid follicular cell that mediates active iodide transport from the bloodstream to the thyroid follicular cells in the first step and the rate-limiting step of thyroid hormonogenesis [11]. The carboxy-terminus of the protein, which is oriented toward the cytoplasm, contains specific sorting and retention signals required for NIS expression at the basolateral plasma membrane [12, 13, 14, 15]. NIS-mediated active iodide transport is electrogenic and couples the inward translocation of one iodide ion against its electrochemical gradient to the inward transport of two sodium ions down its electrochemical gradient, generated by the sodium/potassium ATPase [16]. Remarkably, NIS transports iodide efficiently at the submicromolar concentrations found in the bloodstream, by taking advantage of the physiological sodium concentration [17]. Therefore, the mechanism of NIS-mediated iodide transport seems to be an evolutionary adaptation to the scant amount of iodide in the environment.

In addition to the different radioiodide isotopes, NIS can translocate a variety of clinically relevant radionuclide substrates. These include ^99mTc-pertechnectate or ¹⁸F-tetrafluoroborate, which facilitates noninvasive diagnostic imaging, and also ¹⁸⁸Re-perrhenate, which allows therapeutic destruction of tumor tissue through the radionuclide accumulation of NIS-expressing cells and the bystander effect induced by the crossfire effect of beta emission [10].

Underscoring the significance of NIS for thyroid physiology, several naturally occurring loss-of-function NIS variants have been identified as causes of the uncommon autosomal recessive disorder iodide transport defect, which results in dyshormonogenic congenital hypothyroidism due to insufficient iodide availability for thyroid hormonogenesis [9]. Moreover, a recent study speculated that pathogenic variants may exist in yet to be discovered thyroid-specific genes and are likely to be required for NIS-mediated iodide transport in the thyroid follicular cell [18]. In line with this hypothesis, the KCNQ1/KCNE2 potassium channel has been shown to be required for adequate NIS-mediated iodide accumulation in the thyroid tissue [19, 20]. The detailed functional characterization of loss-of-function NIS variants identified in patients has provided mechanistic information about the transporter. Remarkably, several amino acid residues have been identified as being critical for substrate binding, specificity, and stoichiometry, as well as for folding and plasma membrane targeting [21, 22, 23, 24, 25, 26, 27, 28].

Once iodide has reached the cytosol of the thyroid follicular cells, the iodide is then handled by a sophisticated thyroid-specific iodine-metabolizing machinery that covalently incorporates (also named organification) iodine into tyrosine residues of thyroglobulin, which permits further thyroid hormone synthesis [29]. Significantly, the normal function of this iodide-metabolizing machinery is not only critical for thyroid hormonogenesis, but also for successful radioiodine ablation of cancer cells, as the covalent incorporation of radioiodine into thyroglobulin increases the residence time of the radioisotope.

3. Radioiodine therapy

Radioiodine therapy relies on the unique property of the thyroid follicular cell to transport and incorporate iodide into thyroglobulin, a feature that is maintained in a subgroup of differentiated thyroid carcinomas. Postoperative radioiodine administration can be used to destroy presumably benign residual thyroid tissue (remnant ablation), to destroy suspected but not identified remaining disease (adjuvant treatment), and to destroy known residual or recurrent disease (treatment) [30]. Until recently, most patients with differentiated thyroid carcinoma received postoperative radioiodine therapy, constituting a standard of care. Nowadays, radioiodine therapy has been personalized based on the risk of recurrence stratification and the prognostic indicators obtained during thyroidectomy and also on the findings of postoperative neck ultrasound and serum thyroglobulin levels. Radioiodine therapy is currently exceptionally recommended in patients with low-risk thyroid cancers, which represents the majority of patients with thyroid cancer.

Radioiodine is administered following thyrotropin (TSH) stimulation, the primary regulator of NIS expression in the thyroid follicular cell at both the transcriptional and posttranscriptional levels. TSH stimulation is achieved either by long-term withdrawal of thyroid hormone replacement treatment or after recombinant human TSH treatment. The use of recombinant human TSH avoids symptoms of hypothyroidism, thereby improving the quality of life of the patients [31]. Restriction of dietary iodine is often recommended, and iodinated radiocontrast agents should be excluded before radioiodine scanning or treatment of differentiated thyroid carcinomas to avoid isotopic dilution, thus possibly improving radioiodine therapy efficacy [32].

Papillary thyroid carcinoma, the most prevalent form of the disease and accounting for approximately 85% of differentiated thyroid carcinomas, includes several tumor subtypes of which ~70% have mutually exclusive mutations of gene-encoding effectors of the mitogen-activated protein kinase (MAPK) signal pathway [33]. The papillary thyroid cancer genome atlas has revealed that the main genomic alterations include point mutations in the proto-oncogenes BRAF and (N, H, or K) RAS and also chromosomal rearrangements involving the proto-oncogenes RET and NTRK [34]. Significantly, BRAFV600E-harboring papillary thyroid carcinomas frequently have a poor response to radioiodine therapy [35]. Related to this, their refractoriness to radioiodine appears to be due to the strong BRAFV600E-triggered MAPK-dependent transcriptional program suppressing (or even abolishing) the expression of genes involved in iodide uptake and metabolism, which are hallmarks of the differentiated state of thyroid follicular cells. In contrast, RAS-mutated papillary thyroid carcinomas show a low MAPK-dependent transcriptional program (due to negative feedback regulation), retaining the expression of iodine-metabolism genes, and are usually radioiodine-avid [36]. Low frequency types of differentiated thyroid carcinomas, such as Hürthle-cell carcinomas and poorly differentiated thyroid carcinomas, are particularly refractory to radioiodine therapy.

Since, as mentioned above, BRAFV600E is frequently associated with decreased responsiveness to radioiodine, an emerging clinically relevant question is whether genetic markers can reliably predict the radioiodine refractoriness of thyroid carcinomas [37]. Indeed, recent studies have demonstrated that ~70% of patients with metastatic papillary thyroid cancer carrying the oncogene BRAFV600E do not demonstrate any radioiodine uptake, with this percentage increasing up to 97% when BRAFV600E is associated with mutations in the promoter of the Telomerase Reverse Transcriptase (TERT) [38, 39]. However, a subset of BRAFV600E-carrying papillary thyroid carcinomas does respond to radioiodide therapy [36]. Significantly, the BRAFV600E-containing papillary thyroid tumors that showed better responses to radioiodine therapy also revealed a relatively preserved expression of thyroid differentiation genes, and a higher expression of microRNAs targeting the transforming growth factor β (TGFβ) signaling pathway, which when activated repressed thyroid-specific gene expression [40].

4. Radioiodine-refractory thyroid cancer

Approximately 80 years after the first clinical use of radioiodine therapy for the diagnosis and treatment of differentiated thyroid cancer [41], radioiodine therapy is still the first choice of treatment after thyroidectomy for primary and metastatic differentiated thyroid carcinomas. However, 30% of metastatic differentiated thyroid tumors show dedifferentiation and lose their ability to accumulate radioiodine, thus making adjuvant treatment with radioiodine ineffective (radioiodine-refractory) [42]. Current therapeutic strategies for symptomatic radioiodine-refractory thyroid cancers include the implementation of local therapy whenever possible. However, in the case of diffuse significant progression of distant metastatic disease, systemic therapy is currently based on anti-angiogenic multi-targeted tyrosine kinase inhibitors [43]. The two multi-targeted tyrosine kinase inhibitors sorafenib and lenvatinib have been approved by regulatory authorities for use in radioiodine-refractory differentiated thyroid carcinomas [44, 45]. These agents have shown promising results with a significant improvement of median progression-free survival over placebo, but generally with similar overall survival. More recently, novel highly selective inhibitors targeting oncogenic chromosomal rearrangements involving the proto-oncogenes RET and NTRK have been approved for clinical use in radioiodine-refractory differentiated thyroid carcinomas [46, 47]. Therefore, the presence of druggable oncogenes should be screened in patients with metastatic disease, and whenever present, a selective inhibitor might be considered.

The underlying molecular basis for the loss of radioiodine accumulation in radioiodine-refractory metastatic thyroid carcinomas is thyroid dedifferentiation, which results in a decreased expression of the genes involved in the iodide metabolism. Radioiodine therapy effectivity is ultimately dependent on functional NIS expression at the plasma membrane of the thyroid tumor cells, as deficient radioiodide accumulation is the major cause of treatment failure [5]. However, NIS gene expression is frequently downregulated in differentiated thyroid cancer compared with normal thyroid tissue or even totally silenced as evidenced in poorly differentiated carcinomas. Multiple transcriptional and posttranscriptional mechanisms have been postulated to explain NIS gene repression in thyroid tumors, including transcriptional repression of the transcription factor Pax8 that regulates NIS gene transcriptional expression, and by TGFB1-induced activation of SMAD signaling leading to NOX4-dependent ROS production, which in turn impairs Pax8-dependent NIS gene expression [48, 49]. Immunohistochemical studies have revealed that NIS is frequently expressed (or even overexpressed) at different levels in differentiated thyroid carcinomas compared with adjacent normal tissue [50]. However, NIS expression is mainly located in intracellular compartments, indicating that a posttranslational mechanism is involved in radioiodide resistance due to defective NIS expression at the plasma membrane [51, 52]. Significantly, loss-of-function NIS variants have not been identified in either benign cold thyroid nodules or thyroid tumors [53, 54], demonstrating that the intracellular retention of NIS is not caused by structural defects, as reported in patients with dyshormonogenic congenital hypothyroidism. Therefore, the paradoxical observation of reduced radioiodine uptake and intracellularly retained NIS protein expression highlights the importance of elucidating the posttranslational mechanisms regulating NIS plasma membrane expression.

The pituitary tumor-transforming gene (PTTG) binding factor (PBF) has been reported as being an NIS-interacting protein involved in NIS intracellular retention in thyroid cancer, as ectopic PBF overexpression results in reduced iodide accumulation caused by NIS endocytosis from the plasma membrane [55]. The phosphorylation of the PBF residue Tyr-174 is required for PBF-mediated NIS endocytosis, as PP1-inhibited Src kinase activity restores iodide accumulation in thyroid cancer cell lines [56]. Moreover, chemical inhibition of the NIS-interacting protein valosin-containing protein (VCP), a principal component of the endoplasmic reticulum-associated degradation protein quality control process involved in NIS proteolysis, increases NIS expression at the plasma membrane and radioiodide accumulation in thyroid cancer models [57]. Recently, high-throughput drug screening has revealed multiple cellular processes that are central to NIS regulation, including proteasomal degradation and autophagy, which can be drugged to enhance radioiodide uptake [58]. Moreover, functional defects in the glycosylphosphatidylinositol (GPI) transamidase complex due to BRAF^V600E-triggered PIGU repression cause partially glycosylated NIS molecules to be retained in the endoplasmic reticulum, probably due to a deficiency in an unidentified GPI-anchored protein that is necessary for proper NIS anterograde plasma membrane transport [59].

Constitutive activation of mitogen-activated protein kinase (MAPK) signaling induces a partial to complete loss of differentiation in thyroid cancers. In agreement, in vitro studies have revealed that BRAFV600E impairs NIS expression, thereby reducing iodide uptake [60]. In patients, BRAFV600E expression in papillary thyroid carcinoma was correlated with radioiodine-refractory recurrences and defective NIS expression or intracellular retention [61]. In line with this, transgenic mice expressing the oncogene BRAFV600E in thyroid follicular cells developed papillary thyroid tumors, with these tumors neither concentrating radioiodine nor responding to radioiodine therapy [62]. Interestingly, the blockage of BRAFV600E kinase activity with either the BRAFV600E-selective ATP competitive inhibitor PLX4720, a vemurafenib progenitor, or further downstream with the allosteric MEK 1/2 kinase inhibitor selumetinib, restored thyroid-specific gene expression (including NIS) and radioiodine incorporation into these tumors, which rendered them susceptible to therapeutic doses of radioiodine [62].

When used as single agents, vemurafenib and selumetinib are comparatively ineffective inhibitors of BRAFV600E-driven thyroid cancer. Although they are potent inhibitors of MAPK-ERK signaling in thyroid cancer, this inhibition is followed by a strong rebound effect that reactivates ERK signaling. Blockage of ERK-dependent negative feedback mechanisms increases the expression of the tyrosine kinase HER3, with its activation after dimerization with HER2 by the autocrine-secreted ligand neuregulin leading to ERK activation involving CRAF signaling [63]. Significantly, the allosteric MEK 1/2 inhibitor CH5126766, when bound to the protein, impairs its phosphorylation by upstream (A, B, or C) RAF kinases and reduces reactivation of ERK signaling, which overcomes the adaptive resistance of BRAFV600E-promoted thyroid cancer to MAPK inhibitors and markedly enhances the effectiveness of radioiodine therapy [64].

5. Redifferentiation therapy

Recent progress in understanding the molecular mechanisms that repress functional NIS expression has identified possibilities of new therapeutic approaches, which may expand the application of radioiodine therapy to radioiodine-refractory thyroid cancers. Indeed, some emerging therapies using MAPK signal small-molecule inhibitors, which are still in the clinical phase of study, have shown promising effects by restoring radioiodine accumulation in radioiodine-refractory differentiated thyroid cancer metastasis (redifferentiation therapy) [65].

Encouraging preclinical data, suggesting that MAPK signaling inhibition in BRAFV600E-induced thyroid cancer mouse models partially restores radioiodine accumulation [62, 64], has prompted pilot clinical studies in patients with thyroid cancer metastases resistant to radioiodide. In the first pilot clinical trial, selumetinib treatment restored iodide uptake at metastatic sites in 12 out of 20 patients with advanced radioiodine-refractory papillary thyroid cancer, and with eight of these attaining the predefined dosimetry threshold to enable radioiodine therapy with remarkable clinical responses: five of which had partial responses and with the other three having stable disease at 6 months after therapy [66]. Significantly, the therapeutic benefit of selumetinib was dependent on the mutation landscape, as all five patients carrying NRASQ61R/K, but only one of nine patients carrying BRAFV600E, redifferentiated sufficiently to be able to receive radioiodine therapy [66].

The BRAFV600E inhibitor dabrafenib was evaluated in patients with BRAFV600E-containing advanced radioiodine-refractory metastatic papillary thyroid cancer [67]. Dabrafenib treatment restored iodide uptake at metastatic sites in six out of 10 patients, and all these six patients were then treated with radioiodine, leading to a partial response and stable disease in two and four patients, respectively, at 3 months after therapy [67]. In a more recent pilot clinical trial, another BRAF inhibitor, vemurafenib, was evaluated in patients with BRAFV600E-containing advanced radioiodine-refractory metastatic papillary thyroid cancer [68]. Vemurafenib treatment restored or increased radioiodine accumulation in at least one metastatic lesion in six out of 10 patients. Of these, four patients attained the predefined dosimetry threshold and received radioiodide therapy, resulting in disease-free progression, with two confirmed partial responses and two with stable disease at 6 months after therapy [68]. Significantly, a transcriptomic analysis of tumor biopsy revealed that vemurafenib treatment reduced the MAPK pathway transcriptional output and induced thyroid differentiation markers [68].

In an interesting retrospective review of clinical data, six patients with radioiodine-refractory thyroid carcinomas received mutation-guided redifferentiation therapy [69]. Patients with NRASQ61K/R-harboring tumors were treated with the MEK inhibitor trametinib, and those with BRAFV600E received a combination of BRAF and MAPK inhibitors (dabrafenib and trametinib, or vemurafenib and cobimetinib). Redifferentiation therapy restored radioiodine accumulation in one of the three patients with NRASQ61K, and in all three patients with BRAFV600E. Radioiodine therapy was applied to these four patients, with three achieving a partial response and one having a stable disease under a median follow-up of 16.6 months [69]. Significantly, this study suggests that the mutation-guided MAPK pathway combined inhibition is a promising strategy to redifferentiate BRAFV600E radioiodine-refractory thyroid carcinomas, thereby rendering them suitable for radioiodine therapy.

Very recently, the results were published of the first large-scale phase 3 clinical trial conducted to evaluate the clinical benefit of adding selumetinib to adjuvant radioiodine therapy in patients with a high-risk of persistent disease or disease recurrence following initial total thyroidectomy [70]. Of the 233 patients enrolled, 97% of the placebo group and 83% of the selumetinib group completed the treatment. The complete response rate analysis at 18 months revealed no statistically significant improvement in response to selumetinib therapy compared with placebo.

The adaptive resistance to MAPK inhibitors driven by neuregulin-dependent HER3/HER2 activation observed in BRAF-mutated thyroid cancers led to testing the strategy of combining MAPK inhibitors with EGF receptor (HER) inhibitors. Significantly, the HER kinase inhibitor lapatinib prevented MAPK rebound and overcame BRAFV600E thyroid cancer cell resistance to MAPK inhibitors [63]. Similarly, in BRAFV600E expressing human thyroid cancer cell lines, the combination of lapatinib with dabrafenib or selumetinib increased radioiodine accumulation [71]. Based on the abovementioned preclinical data, a recent small pilot clinical trial assessed vemurafenib in combination with ErbB3 targeting of monoclonal antibody CDX-3379 in radioiodine-refractory metastatic thyroid cancer carrying BRAFV600E [72]. This combined therapy increased radioiodine accumulation in five out of six patients, of which four patients had a sufficient reaction to warrant radioiodine therapy. At 6 months post-therapy, two of these patients achieved a confirmed partial response [72].

Recently, Saqsena et al. [73] investigated the impact of the SWItch/Sucrose Non-Fermentable (SWI/SNF) chromatin remodeling complex on BRAFV600E-driven thyroid cancer differentiation. Mechanistically, the functional loss of different SWI/SNF subunits reduced the expression of thyroid differentiation markers by repressing chromatin accessibility to the gene encoding different transcription factors required for expression of genes regulating iodide transport and metabolism. Importantly, SWI/SNF loss promoted resistance to MAPK inhibitor–based redifferentiation therapies, reducing the effectiveness of radioiodine treatment [73]. Moreover, the preclinical data suggest that mutations affecting individual SWI/SNF complex subunits should be investigated as potential markers of resistance to redifferentiation strategies, as patients with radioiodine-refractory tumors carrying biallelic mutations in the SWI/SNF complex genes ARID1A, ARID2, or SMARCB1 failed to show a clinically significant restoration of radioiodine incorporation in response to MAPK pathway inhibition [72, 73].

The development of well-tolerated systemic therapies that selectively target oncogenic chromosomal rearrangements involved in thyroid carcinogenesis has extended the landscape of therapeutic opportunities in radioiodine-refractory thyroid carcinomas [46, 47]. Recently, different clinical case reports have revealed that the selective NTRK inhibitor larotrectinib restored radioiodine accumulation in radioiodine-refractory lung metastases harboring the NTRK fusions EML4-NTRK3, TPR-NTRK1, ETV6-NTRK3, and TPM3-NTRK1 [74, 75, 76]. Likewise, the selective RET inhibitor selpercantinib restored radioiodine accumulation in radioiodine-refractory lung metastases harboring RET fusions CCDC6-RET and NCOA4-RET [75, 77]. Moreover, a recent report presented the case of a pediatric patient with a TPM3-NTRK1 fusion-positive lung metastatic papillary thyroid carcinoma, who received redifferentiation therapy with larotrectinib as a neoadjuvant systemic approach, before the initial dose of radioiodine [78].

6. Conclusions

Radioiodine accumulation in the thyroid tissue has been exploited in clinical medicine in the diagnosis and treatment of thyroid pathologies for several decades, even before the molecular characterization of the mechanism mediating iodide accumulation. Since the cloning of NIS, significant progress has been made in understanding the mechanisms mediating the resistance to radioiodine therapy, with the efficacy of the therapy having been shown to be directly related to the therapeutic dose of radiation delivered to tumor cells [79]. From a therapeutic perspective, improving radioiodine therapy for thyroid cancer is a priority for developing strategies aimed not only at enhancing radioiodine accumulation but also for promoting efficient radioiodine organification for its retention inside thyroid tumor cells, in order to improve radiation dose delivery to provide better treatment efficacy. Significantly, experimental models have revealed that phosphoinositide 3-kinase (PI3K) inhibitors seem to prolong radioiodine retention in thyroid cells [80].

The understanding of the molecular events involved in the biology of thyroid cancer has rapidly expanded the therapeutic landscape for the treatment of iodine-refractory thyroid cancer. Redifferentiation therapy has emerged as an attractive alternative in the clinical management of radioiodine-refractory thyroid carcinomas, but the promising clinical data are still preliminary. However, monotherapy with MAPK inhibitors only increases iodide accumulation in a marginal fraction of patients with metastatic thyroid cancers expressing BRAFV600E, probably due to incomplete MAPK signaling inhibition, thus suggesting that profound inhibition of MAPK signaling is required for treating these tumors effectively. The identification of novel small-molecule inhibitors exhibiting a stronger and sustained inhibition of MAPK signaling may provide novel alternatives for maximizing the response to radioiodine therapy.

An emerging topic is the value of genetic marker-based precision management of radioiodine therapy in thyroid cancer. The co-occurrence of TERT promoter mutations in BRAFV600E-carrying recurrent papillary thyroid carcinomas is associated with loss of radioiodine accumulation. Moreover, the functional loss of SWI/SNF subunits may mediate resistance to redifferentiation therapies and might serve as biomarkers for identifying patients who will not benefit from this therapy. Although large clinical trials are necessary to validate this hypothesis, the presence of deleterious SWI/SNF subunit lesions may prompt physicians to consider treatments other than radioiodide.

Acknowledgments

We are grateful to Dr. Ana María Masini-Repiso (National University of Córdoba, Argentina) for critical reading of the manuscript. This work was supported by Fondo para la Investigación Científica y Tecnológica - Agencia Nacional de Promoción Científica y Tecnológica (grants number PICT-2018-1596, PICT-2019-1772, PIDC-2019-0007, and PICT-2021-0005).

Conflict of interest

The authors declare no conflict of interest.