Selpercatinib-induced hypothyroidism through off-target inhibition of type 2 iodothyronine deiodinase Journal Article
| Authors: | Boucai, L.; Salas-Lucia, F.; Krishnamoorthy, G. P.; Sherman, E.; Rudin, C. M.; Drilon, A.; Bianco, A. C.; Fagin, J. A. |
| Article Title: | Selpercatinib-induced hypothyroidism through off-target inhibition of type 2 iodothyronine deiodinase |
| Abstract: | PURPOSE The 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 METHODS Thyroid 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. RESULTS Upon 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. CONCLUSION An 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. (c) 2022 by American Society of Clinical Oncology |
| Keywords: | thyroxine; pituitary; loxo-292 |
| Journal Title: | JCO Precision Oncology |
| Volume: | 6 |
| ISSN: | 2473-4284 |
| Publisher: | American Society of Clinical Oncology |
| Date Published: | 2022-01-01 |
| Start Page: | e2100496 |
| Language: | English |
| ACCESSION: | WOS:000975488400014 |
| DOI: | 10.1200/po.21.00496 |
| PROVIDER: | wos |
| PMCID: | PMC9384953 |
| PUBMED: | 35704797 |
| Notes: | The MSK Cancer Center Support Grant (P30 CA008748) is acknowledged in the PDF. Corresponding author is MSK author Laura Boucai -- Source: Wos |
Altmetric
Citation Impact
BMJ Impact Analytics
Related MSK Work