RET is a receptor tyrosine kinase that plays an important role in the development of neurons and kidneys. The gene encoding the rearranged-during-transfection (RET) receptor tyrosine kinase was first discovered in the 1980s. ActivatingRETmutations and rearrangements have since been identified as actionable drivers of oncogenesis in numerous cancer types and are most prevalent in thyroid and non-small-cell lung cancer. Following the modest success of repurposed RET-active multikinase inhibitors, the first selective RET inhibitors (SRIs), selpercatinib and pralsetinib, received regulatory approval in 2020. Now, thousands of patients with RET-altered cancers have benefited from first-generation SRIs, with impressive deep and durable responses. However, following prolonged treatment with these SRIs, a number of acquired on-target resistance mutations have been identified together with other non-RET-dependent resistance mechanisms. Today, the focus is on how we can further evolve and improve the treatment of RET-altered tumors with next-generation SRIs, and a number of candidate drugs are in development. The ideal next-generation SRIs will be active against on-target acquired resistance alterations, including those that emerge in the CNS, and will have improved safety and tolerability relative to first-generation SRIs. In this review, we will provide an update on these candidates and their potential to meet the unmet clinical need for patients who progress on first-generation SRIs.
RET是一种受体酪氨酸激酶，在神经元和肾脏发育中发挥重要作用。编码重排转染（RET）受体酪氨酸激酶的基因于20世纪80年代首次被发现。随后，激活型RET突变和重排被确认为多种癌症类型中可干预的致癌驱动因素，在甲状腺癌和非小细胞肺癌中最为常见。在非特异性RET活性多激酶抑制剂取得有限疗效后，首个选择性RET抑制剂（SRIs）——塞尔帕替尼和普拉替尼于2020年获得监管批准。目前，已有数千名RET变异癌症患者从第一代SRIs中获益，展现出显著且持久的深度缓解。然而，随着这些SRIs的长期使用，一系列获得性靶向耐药突变及其他非RET依赖性耐药机制逐渐显现。当前的研究重点在于如何通过下一代SRIs进一步优化和改进RET变异肿瘤的治疗策略，多种候选药物正处于研发阶段。理想的下一代SRIs应能有效应对获得性靶向耐药变异（包括中枢神经系统内出现的变异），同时相较于第一代SRIs具有更优的安全性和耐受性。本综述将更新这些候选药物的最新进展，并探讨其满足第一代SRIs治疗进展患者未满足临床需求的潜力。
肿瘤(癌症)患者之家