Medical Oncology Department, Hospital Universitario Ramón y Cajal, 28034 Madrid, Spain.
Pathology Department, Hospital Universitario Ramón y Cajal, 28034 Madrid, Spain.
Cancer Treat Rev. 2022 Apr;105:102372. doi: 10.1016/j.ctrv.2022.102372. Epub 2022 Mar 1.
Thyroid cancer is the most frequently diagnosed endocrine malignancy, with an increasing incidence over the last decades. The recent advances in understanding the molecular mechanisms underlying the carcinogenesis of thyroid cancer have led to a better therapeutic approach of these tumors. This has allowed the development and approval of several drugs during the past decade. The rearranged during transfection [RET] protooncogene encodes a transmembrane receptor tyrosine kinase, which is activated by chromosomal rearrangements or point mutations in multiple malignancies, including thyroid cancer. Selective RET inhibitors have proved their value in the treatment algorithm in molecularly selected patients with significantly high response rates and duration of response. Notwithstanding, there are patients who experiment rapid progression or tumor recurrence after an early response to those targeted therapies, which suggest the existence of primary and acquired mechanisms of resistance that have been largely unknown to date. In the present review, we attempt to provide a comprehensive analysis of the most relevant mechanisms of resistance to RET inhibitors which could help in the development of next generation MKI and RET inhibitors, along with combination strategies with different targeted therapies that could potentially overcome these resistances.
甲状腺癌是最常见的内分泌恶性肿瘤，在过去几十年中发病率不断上升。近年来，对甲状腺癌发生的分子机制的理解取得了进展，这为这些肿瘤的治疗方法提供了更好的选择。这使得在过去十年中开发并批准了几种药物。重排基因在转染期间[RET]原癌基因编码一种跨膜受体酪氨酸激酶，它在多种恶性肿瘤中，包括甲状腺癌，通过染色体重排或点突变而被激活。选择性 RET 抑制剂已被证明在分子选择的患者的治疗方案中具有价值，这些患者的反应率和反应持续时间显著较高。尽管如此，仍有一些患者在对这些靶向治疗早期反应后经历快速进展或肿瘤复发，这表明存在目前尚未完全了解的原发性和获得性耐药机制。在本综述中，我们试图对 RET 抑制剂耐药的最相关机制进行全面分析，这有助于开发下一代 MKI 和 RET 抑制剂，以及与不同靶向治疗相结合的策略，这些策略可能会克服这些耐药性。
