文章：

非小细胞肺癌中RET基因融合的发现历程至新型高效选择性RET抑制剂的问世：“迷雾与阴影”

Non-Small-Cell Lung Cancers (NSCLCs) Harboring RET Gene Fusion, from Their Discovery to the Advent of New Selective Potent RET Inhibitors: “Shadows and Fogs”

原文发布日期：19 August 2024

DOI: 10.3390/cancers16162877

类型: Article

开放获取: 是

英文摘要：

RET fusions are relatively rare in Non-Small-Cell Lung Cancers (NSCLCs), being around 1–2% of all NSCLCs. They share the same clinical features as the other fusion-driven NSCLC patients, as follows: younger age, adenocarcinoma histology, low exposure to tobacco, and high risk of spreading to the brain. Chemotherapy and immunotherapy have a low impact on the prognosis of these patients. Multitargeted RET inhibitors have shown modest activity jeopardized by high toxicity. New potent and selective RET inhibitors (RET-Is) (pralsetinib and selpercatinib) have achieved a higher efficacy minimizing the known toxicities of the multitargeted agents. This review will describe the sensitivity of immune-checkpoint inhibitors (ICIs) in RET fusion + NSCLC patients, as well their experiences with the ‘old’ multi-targeted RET inhibitors. This review will focus on the advent of new potent and selective RET-Is. We will describe their efficacy as well as the main mechanisms of resistance to them. We will further proceed to deal with the new drugs and strategies proposed to overcome the resistance to RET-Is. In the last section, we will also focus on the safety profile of RET-Is, dealing with the main toxicities as well as the rare but severe adverse events.

摘要翻译： 

RET融合在非小细胞肺癌（NSCLC）中相对罕见，约占所有NSCLC的1%-2%。与其他融合驱动型NSCLC患者相似，此类患者具有以下临床特征：发病年龄较轻、组织学类型为腺癌、烟草暴露程度低且脑转移风险较高。化疗与免疫疗法对这些患者的预后改善作用有限。多靶点RET抑制剂虽有一定疗效，但高毒性限制了其临床应用。新型高效选择性RET抑制剂（如普拉替尼和塞普替尼）在显著提升疗效的同时，最大限度降低了多靶点药物已知的毒性风险。本综述将阐述免疫检查点抑制剂在RET融合阳性NSCLC患者中的敏感性，并总结传统多靶点RET抑制剂的应用经验。重点聚焦新型高效选择性RET抑制剂的出现，系统阐述其疗效及主要耐药机制，进一步探讨克服RET抑制剂耐药的新药研发策略与治疗方案。最后部分将深入分析RET抑制剂的安全性特征，包括主要毒性反应及罕见但严重的不良事件。

原文链接：

Non-Small-Cell Lung Cancers (NSCLCs) Harboring RET Gene Fusion, from Their Discovery to the Advent of New Selective Potent RET Inhibitors: “Shadows and Fogs”