Thyroid Neoplasia Unit, Department of Clinical Therapeutics, National Kapodistrian University of Athens, Medical School, Athens, Greece.
Department of Endocrinology, 401 Military Hospital, Athens, Greece.
Eur J Endocrinol. 2022 Jul 26;187(3):R53-R63. doi: 10.1530/EJE-22-0312. Print 2022 Sep 1.
During the last decades, knowledge of the molecular biology in medullary thyroid carcinoma (MTC) and specifically on the role of rearranged during transfection (RET)-activating mutations in tumorigenesis has led to the evolution of novel targeted therapies, mainly tyrosine kinase inhibitors (TKIs). Vandetanib and cabozantinib have been approved for the management of metastatic progressive MTC. Two novel, highly selective RET inhibitors, selpercatinib and pralsetinib, have recently been approved for the treatment of RET-mutant MTCs and RET-fusion differentiated thyroid cancer. The administration of targeted therapies in MTC patients has changed the therapeutic strategies; however, in the majority of cases, there are no real data showing an improvement of prognosis by TKIs in MTC. Drug resistance remains the main reason for treatment failure. Thus, the understanding of the molecular landscape of tumorigenesis and the mechanisms underlying resistance to targeted therapies is of paramount importance for the further development of more efficient therapies for MTC. The present review focuses on the molecular pathways implicated in MTC tumorigenesis, the approved targeted therapies, the tumoral escape mechanisms, as well as the future perspectives for targeted therapy.
在过去的几十年中，对甲状腺髓样癌（MTC）的分子生物学的认识，特别是在肿瘤发生过程中转录后重排（RET）激活突变的作用方面的认识，导致了新型靶向治疗方法的发展，主要是酪氨酸激酶抑制剂（TKI）。凡德他尼和卡博替尼已被批准用于治疗转移性进展性 MTC。两种新型、高度选择性的 RET 抑制剂——塞尔帕替尼和普拉替尼最近已被批准用于治疗 RET 突变型 MTC 和 RET 融合型分化型甲状腺癌。MTC 患者的靶向治疗的应用改变了治疗策略；然而，在大多数情况下，没有真实的数据表明 TKI 可以改善 MTC 的预后。耐药性仍然是治疗失败的主要原因。因此，了解肿瘤发生的分子景观和对靶向治疗的耐药机制对于进一步开发更有效的 MTC 治疗方法至关重要。本文综述了涉及 MTC 肿瘤发生的分子途径、已批准的靶向治疗方法、肿瘤逃逸机制以及靶向治疗的未来前景。
