塞来昔替尼导致的甲状腺功能减退症：通过对 2 型甲状腺素脱碘酶的非靶标抑制。
Selpercatinib-Induced Hypothyroidism Through Off-Target Inhibition of Type 2 Iodothyronine Deiodinase.
机构信息
Department of Medicine, Division of Endocrinology, Memorial Sloan Kettering Cancer Center, New York, NY.
Department of Medicine, Division of Endocrinology, University of Chicago, Chicago, IL.
出版信息
JCO Precis Oncol. 2022 Jun;6:e2100496. doi: 10.1200/PO.21.00496.
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.
目的
选择性 RET 抑制剂塞尔帕替尼和普拉替尼的开发彻底改变了转移性进行性 RET 突变型甲状腺髓样癌（MTC）和其他 RET 驱动型癌症的治疗方法，因为它们具有更有利的副作用谱。本研究旨在研究在无甲状腺的 RET 突变型 MTC 患者和具有功能性甲状腺的 RET 突变型非小细胞肺癌（NSCLC）患者中，塞尔帕替尼引起甲状腺功能障碍的机制。
材料和方法
在一项观察性队列研究中，评估了五例无甲状腺的 MTC 患者和 30 例 NSCLC 患者在开始使用塞尔帕替尼前后的甲状腺激素水平。在表达内源性 D1、D2 和 D3 碘甲状腺原氨酸脱碘酶的细胞中进行了体外实验，以确定塞尔帕替尼引起甲状腺功能障碍的机制。
结果
在开始使用塞尔帕替尼治疗后，无甲状腺的患者出现临床甲状腺功能减退症，尽管补充了足够的左甲状腺素，但 T3 水平降低了约 60%，而在保留正常甲状腺的 NSCLC 患者中，塞尔帕替尼导致血清 T3 水平降低更为减弱，且呈剂量依赖性。我们对表达 D1、D2 或 D3 的细胞进行了研究，这三种碘甲状腺原氨酸脱碘酶。塞尔帕替尼抑制 MSTO-211 细胞中 D2 介导的 T3 产生 50%。在表达 RET 的人甲状腺癌 TT 细胞中存在 D2 mRNA 的适度抑制，但在不表达 RET 的 MSTO-211 细胞中不存在。该药物对 D1（激活脱碘酶）或 D3（失活脱碘酶）无影响。因此，塞尔帕替尼对 D2 活性的非转录效应最可能解释 T3 水平降低的原因。
结论
塞尔帕替尼对 D2 介导的 T3 产生的非靶向作用导致甲状腺功能减退症，主要发生在接受左甲状腺素治疗的无甲状腺患者中。需要补充三碘甲状腺原氨酸以达到正常 T3 水平并恢复临床甲状腺功能正常。
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