Since the discovery in 2012 of rearranged during transfection proto-oncogene gene (RET) rearrangements in NSCLC, at least 12 different fusion variants have been identified, with kinesin family member 5B gene (KIF5B)-RET being the most frequent and the best characterized. Unlike ALK receptor tyrosine kinase gene (ALK) and ROS1 rearrangements, RET fusion genes cannot be adequately detected by immunohistochemistry (IHC), although fluorescence in situ hybridization and reverse transcriptase polymerase chain reaction are fully complementary diagnostic tools. In large retrospective studies, RET rearrangements correlate with adenocarcinoma histologic subtype, never-smoking status, younger age, more advanced disease stage, potentially higher chemosensitivity (in particular, to pemetrexed-based regimens), and coexistence of other genomic alterations. To date, several preclinical models, clinical trials, and retrospective studies have investigated multitarget inhibitors with anti-rearranged during transfection proto-oncogene (RET) activity in patients with RET-rearranged lung cancer. In the clinical setting, the benefit in terms of response (16%-47%) and progression-free survival (2-7 months) is clearly not comparable to that seen with other targeted agents in oncogene-addicted NSCLC. Furthermore, multikinase agents showed high rates of severe toxicities, leading to frequent dose reduction and drug discontinuation. To date, no definitive conclusions about a potentially different impact of anti-RET therapies according to RET fusion variants have been drawn on account of discordant data coming mostly from small subgroup analyses. Importantly, the absence of a striking clinical benefit in RET oncogene-addicted NSCLC underscores the clear need for development of more selective and potent RET inhibitors and for better characterization of concomitant genomic alterations and mechanisms of resistance to RET inhibition in patients with lung cancer.

中文翻译：

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RET 重排在非小细胞肺癌中的临床和转化意义

自 2012 年在 NSCLC 中发现转染原癌基因 (RET) 重排过程中发生重排以来，至少已鉴定出 12 种不同的融合变体，其中驱动蛋白家族成员 5B 基因 (KIF5B)-RET 是最常见且表征最好的。与 ALK 受体酪氨酸激酶基因 (ALK) 和 ROS1 重排不同，尽管荧光原位杂交和逆转录酶聚合酶链反应是完全互补的诊断工具，但免疫组织化学 (IHC) 无法充分检测到 RET 融合基因。在大型回顾性研究中，RET 重排与腺癌组织学亚型、从不吸烟状态、年龄较小、疾病分期较晚、可能更高的化学敏感性（特别是对基于培美曲塞的方案）以及其他基因组改变的共存相关。迄今为止，一些临床前模型、临床试验和回顾性研究已经在 RET 重排的肺癌患者中研究了在转染过程中具有抗重排的多靶点抑制剂原癌基因 (RET) 活性。在临床环境中，在反应 (16%-47%) 和无进展生存期 (2-7 个月) 方面的益处显然无法与其他靶向药物在致癌基因成瘾的 NSCLC 中看到的相比。此外，多激酶药物表现出很高的严重毒性，导致频繁的剂量减少和停药。迄今为止，由于主要来自小亚组分析的不一致数据，尚未得出关于根据 RET 融合变体的抗 RET 疗法潜在不同影响的明确结论。重要的，