ArticleJCO precision oncology2022
Selpercatinib-Induced Hypothyroidism Through Off-Target Inhibition of Type 2 Iodothyronine Deiodinase.
Article in JCO precision oncology, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed, 19 citations in OpenAlex.
- How to manage medullary thyroid carcinoma: current treatment strategies.Drugs in context · 2026Review
- Thyroid hormone promotes fetal neurogenesis.JCI insight · 2025Article
- FT3 and FT3/FT4 ratio are decreased and not compensated by levothyroxine treatment in TKI-treated thyroid cancer patients.Endocrine-related cancer · 2025Article
- Molecular Landscape and Therapeutic Strategies in Pediatric Differentiated Thyroid Carcinoma.Endocrine reviews · 2025Review
- FVB But Not B6 Mice Carrying the Thr92Ala-Dio2 Polymorphism Have Impaired Thyroid Hormonogenesis and Goiter.Endocrinology · 2025Article
- Selpercatinib prior to radioactive iodine for pediatric papillary thyroid carcinoma.Journal of pediatric endocrinology & metabolism : JPEM · 2024Article
- Review
- Tyrosine kinase inhibitor-induced hypothyroidism: mechanism and clinical implications.European journal of clinical pharmacology · 2024Review
- Impaired T3 uptake and action in MCT8-deficient cerebral organoids underlie Allan-Herndon-Dudley syndrome.JCI insight · 2024Article
- Strategies for mitigating adverse events related to selective RET inhibitors in patients with RET-altered cancers.Cell reports. Medicine · 2023Review
- Effect of the Fetal THRB Genotype on the Placenta.The Journal of clinical endocrinology and metabolism · 2023Article
- Review
- Article
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Authors and funding
8 authors at 2 institutions in 1 country.
Funding
Abstract
purposeThe development of the selective RET inhibitors selpercatinib and pralsetinib has revolutionized the treatment of metastatic progressive RET-mutant medullary thyroid carcinoma (MTC) and other RET-driven cancers, given their more favorable side-effect profile. The aim of this study is to investigate the mechanisms of selpercatinib-induced thyroid dysfunction in athyreotic patients with RET-mutant MTC and in patients with RET-mutant non-small-cell lung cancer (NSCLC) who had a functional thyroid. MATERIALS AND
methodsThyroid hormone levels were evaluated in an observational cohort of five athyreotic patients with MTC and 30 patients with NSCLC before and after initiation of selpercatinib. In vitro experiments to identify the mechanism of selpercatinib-induced thyroid dysfunction were conducted in cells expressing endogenous D1, D2, and D3 iodothyronine deiodinases.
resultsUpon initiating treatment with selpercatinib, athyreotic patients developed clinical hypothyroidism with approximately 60% lower T3 levels despite adequate levothyroxine supplementation, whereas in patients with NSCLC, who retain a normal thyroid, selpercatinib resulted in a more attenuated reduction in serum T3, which was dose-dependent. We conducted studies in cells endogenously expressing either D1, D2, or D3, the three iodothyronine deiodinases. Selpercatinib inhibited D2-mediated T3 production in MSTO-211 cells by 50%. A modest repression of D2 mRNA was present in human thyroid cancer TT cells that express RET, but not in the MSTO-211 cells that do not. No effect of the drug was observed on D1 (activating deiodinase) or D3 (inactivating deiodinase). Thus, a nontranscriptional effect of selpercatinib on D2 activity is the most plausible explanation for the low T3 levels.
conclusionAn off-target effect of selpercatinib on D2-mediated T3 production leads to clinical hypothyroidism, primarily in levothyroxine-treated athyreotic patients. Liothyronine supplementation was needed to achieve normal T3 levels and restore clinical euthyroidism.
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