Redifferentiation of radioiodine-refractory thyroid cancers

Buffet, C; Wassermann, Johanna; Hecht, Fábio; Leenhardt, Laurence; Dupuy, Corinne; Groussin, Lionel; Lussey-Lepoutre, Charlotte

doi:10.1530/erc-19-0491

Cited by 63 publications

(37 citation statements)

References 144 publications

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“…Furthermore, the impact of effectively targeting essential growth drivers might probably prove to be even more relevant in RAI-rDTC in particular, regarding the potential of possibly inducing redifferentiation and contingent regain of iodine uptake ( Buffet et al 2020 ). The latter, in case it would supervene from the treatment with the drug, may facilitate radioactive-iodine therapy in the patient, and thereby, potentially raising the chances for a cure rather than a prolongation of the progression-free interval ( Buffet et al 2020 ). However, due to practical reasons, we could not investigate this.…”

Section: Discussionmentioning

confidence: 99%

Targeting EML4-ALK gene fusion variant 3 in thyroid cancer

Aydemirli

Eendenburg

Wezel

et al. 2021

Endocrine-Related Cancer

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Finding targetable gene fusions can expand the limited treatment options in radioactive iodine-refractory (RAI-r) thyroid cancer. To that end, we established a novel cell line ‘JVE404’ derived from an advanced RAI-r papillary thyroid cancer (PTC) patient, harboring an EML4-ALK gene fusion variant 3 (v3). Different EML4-ALK gene fusions can have different clinical repercussions. JVE404 cells were evaluated for cell viability and cell signaling in response to ALK inhibitors crizotinib, ceritinib and lorlatinib, in parallel to the patient’s treatment. He received, after first-line lenvatinib, crizotinib (Drug Rediscovery Protocol (DRUP) trial), and lorlatinib (compassionate use). In vitro treatment with crizotinib or ceritinib decreased viability in JVE404, but most potently and significantly only with lorlatinib. Western blot analysis showed a near total decrease of 99% and 89%, respectively, in pALK and pERK expression levels in JVE404 cells with lorlatinib, in contrast to remaining signal intensities of a half and a third of control, respectively, with crizotinib. The patient had a six-month lasting stable disease on crizotinib, but progressive disease occurred, including the finding of cerebral metastases, at 8 months. With lorlatinib, partial response, including clinical cerebral activity, was already achieved at 11 weeks’ use and ongoing partial response at 7 months. To our best knowledge, this is the first reported case describing a patient-specific targeted treatment with lorlatinib based on an EML-ALK gene fusion v3 in a thyroid cancer patient, and own cancer cell line. Tumor-agnostic targeted therapy may provide valuable treatment options in personalized medicine.

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Section: Discussionmentioning

confidence: 99%

Targeting EML4-ALK gene fusion variant 3 in thyroid cancer

Aydemirli

Eendenburg

Wezel

et al. 2021

Endocrine-Related Cancer

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“…BRAF V600E mutation was proposed as a predictor of radioiodine therapy effectiveness in PTC [ 30 ]; however, data undermining this approach also exist [ 31 , 32 ]. What is more, clinical studies which tested the ability of MAPK pathway inhibitors, including BRAF inhibitors, resulted in rather disenchanting effects (as revised in [ 33 ]). Thus, it seems that the presence of a BRAF V600E mutation is not a sufficient condition for resistance to radioiodine therapy.…”

Section: Discussionmentioning

confidence: 99%

MiR-181a-5p Regulates NIS Expression in Papillary Thyroid Carcinoma

Gierlikowski

Broniarek

Cheda

et al. 2021

IJMS

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NIS is a potent iodide transporter encoded by the SLC5A5 gene. Its expression is reduced in papillary thyroid carcinoma (PTC). In this study we analyzed the impact of miR-181a-5p on NIS expression in the context of PTC. We used real-time PCR to analyze the expression of SLC5A5 and miR-181a-5p in 49 PTC/normal tissue pairs. Luciferase assays and mutagenesis were performed to confirm direct binding of miR-181a-5p to the 3′UTR of SLC5A5 and identify the binding site. The impact of modulation of miR-181a-5p using appropriate plasmids on endogenous NIS and radioactive iodine accumulation was verified. We confirmed downregulation of SLC5A5 and concomitant upregulation of miR-181a-5p in PTC. Broadly used algorithms did not predict the binding site of miR-181a-5p in 3′UTR of SLC5A5, but we identified and confirmed the binding site through mutagenesis using luciferase assays. In MCF7 and HEK293-flhNIS cell lines, transfection with mir-181a-expressing plasmid decreased endogenous SLC5A5, whereas silencing of miR-181a-5p increased it. We observed similar tendencies in protein expression and radioactive iodine accumulation. This study shows for the first time that miR-181a-5p directly regulates SLC5A5 expression in the context of PTC and may decrease efficacy of radioiodine treatment. Accordingly, miR-181a-5p may serve as an emerging target to enhance the efficacy of radioactive iodine therapy.

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“…Indeed, in a fraction of patients defined as RAI-resistant, and characterized by low or absent RAI uptake and/or disease persistence or progression following RAI treatment, the prognosis is poor. In these high risk patients who do not respond to RAI [ 16 ], the alternative treatment with systemic therapies based on BRAF or MEK inhibitors, tested as a single agent [ 17 , 18 , 19 ] or in combination (reviewed in [ 20 ]), has been introduced. Along with the anti-tumoral effect, more recently these targeted therapies have also been tested for the possibility of restoring radioiodine sensitivity in RAI-resistant thyroid cancers, and thus, of being exploited as a redifferentiation strategy.…”

Section: Introductionmentioning

confidence: 99%

“…Starting from the observation that different MAPK inhibitors are able to restore NIS expression and/or iodine uptake in various in vitro [ 20 ] and in vivo models [ 22 ] of thyroid cancer, several studies focused on redifferentiation strategies have been undertaken in a clinical setting (reviewed in [ 23 ]). However, limited and variable results were obtained, with RAI uptake restoration only in a fraction of patients and clinical response ranging from partial to null, possibly due to the activation of alternative signaling pathways leading to drug resistance.…”

Section: Introductionmentioning

confidence: 99%

BRAF Inhibitors Induce Feedback Activation of RAS Pathway in Thyroid Cancer Cells

Bonaldi

Gargiuli

Cecco

et al. 2021

IJMS

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BRAFV600E is the most frequent oncogenic mutation identified in papillary thyroid cancer (PTC). In PTC patients who do not respond to standard treatment, BRAF inhibitors are currently tested as alternative strategies. However, as observed for other targeted therapies, patients eventually develop drug resistance. The mechanisms of BRAF inhibitors response are still poorly understood in a thyroid cancer (TC) context. In this study, we investigated in BRAFV600E mutated TC cell lines the effects of Vemurafenib and Dabrafenib, two BRAF inhibitors currently used in a clinical setting. We assessed cell proliferation, and the expression and activity of the thyroid function related transporter NIS following the treatment with BRAF inhibitors. In addition, we investigated the global gene expression by microarray, the relevant modulated biological processes by gene set enrichment analysis (GSEA), and TC specific gene signatures related to MAPK pathway activation, thyroid differentiation, and transcriptional profile associated with BRAFV600E or RAS mutation. We found that both inhibitors induce antiproliferative and redifferentiative effects on TC cells, as well as a rewiring of the MAPK pathway related to RAS signaling. Our results suggest a possible mechanism of drug response to the BRAF inhibitors Vemurafenib or Dabrafenib, supporting very recent findings in TC patients treated with targeted therapies.

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Redifferentiation of radioiodine-refractory thyroid cancers

Cited by 63 publications

References 144 publications

Targeting EML4-ALK gene fusion variant 3 in thyroid cancer

Targeting EML4-ALK gene fusion variant 3 in thyroid cancer

MiR-181a-5p Regulates NIS Expression in Papillary Thyroid Carcinoma

BRAF Inhibitors Induce Feedback Activation of RAS Pathway in Thyroid Cancer Cells

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