虽然在多种癌症中都发现了激活的 RET 融合，但肺癌是最常见的 RET 融合阳性肿瘤。自 2011 年首次在患者肿瘤样本中发现 RET 融合后，RET 融合阳性肺癌的 RET 抑制剂的临床药物开发自然就开始了，此后与 RET 融合阳性甲状腺癌的药物开发同步进行。多激酶抑制剂最初的测试效果有限且毒性很大。随后设计的 RET 抑制剂具有改进的选择性、中枢神经系统外显率以及针对 RET 融合和大多数 RET 突变（包括耐药突变）的活性。由于这些合理设计的特点，第一代选择性 RET 酪氨酸激酶抑制剂 (TKI) 的成功与多激酶抑制剂相比具有更高的缓解率、更持久的疾病控制和更高的安全性。这导致了肺癌和甲状腺癌，以及后来与肿瘤无关的监管批准。虽然下一代 RET TKI 旨在消除对 selpercatinib 和 pralsetinib 不常见的靶向（例如溶剂前突变）耐药性，但其中许多药物缺乏第一代 TKI 的选择性，引发了未来前景的问题RET 依赖性癌症的药物开发。© 2024。作者获得 Springer Nature Switzerland AG 的独家许可。

While activating RET fusions are identified in various cancers, lung cancer represents the most common RET fusion-positive tumor. The clinical drug development of RET inhibitors in RET fusion-positive lung cancers naturally began after RET fusions were first identified in patient tumor samples in 2011, and thereafter paralleled drug development in RET fusion-positive thyroid cancers. Multikinase inhibitors were initially tested with limited efficacy and substantial toxicity. RET inhibitors were then designed with improved selectivity, central nervous system penetrance, and activity against RET fusions and most RET mutations, including resistance mutations. Owing their success to these rationally designed features, the first-generation selective RET tyrosine kinase inhibitors (TKIs) had higher response rates, more durable disease control, and an improved safety profile compared to the multikinase inhibitors. This led to lung and thyroid cancer, and later tumor-agnostic regulatory approvals. While next-generation RET TKIs were designed to abrogate uncommon on-target (e.g., solvent front mutation) resistance to selpercatinib and pralsetinib, many of these drugs lacked the selectivity of the first-generation TKIs, raising the question of what the future holds for drug development in RET-dependent cancers.© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.