RET靶向癌症治疗的进展与挑战

导 读

俄克拉荷马大学健康科学中心Jie Wu教授团队在Frontiers of Medicine发表综述论文《RET靶向癌症治疗的进展与挑战》（Progress and challenges in RET-targeted cancer therapy）。该文综述了RET相关癌症中已获批抑制剂的疗效以及耐药性问题，介绍了新一代抑制剂的研究进展，对深入理解耐药机制、研发联合治疗方案具有重要意义。

The rearranged during transfection (RET) is a receptor protein tyrosine kinase. Oncogenic RET fusions or mutations are found most often in non-small cell lung cancer (NSCLC) and in thyroid cancer, but also increasingly in various types of cancers at low rates. In the last few years, two potent and selective RET protein tyrosine kinase inhibitors (TKIs), pralsetinib (BLU-667) and selpercatinib (LOXO-292, LY3527723) were developed and received regulatory approval. Although pralsetinib and selpercatinib gave high overall response rates (ORRs), < 10% of patients achieved a complete response (CR). The RET TKI-tolerated residual tumors inevitably develop resistance by secondary target mutations, acquired alternative oncogenes, or MET amplification. RET G810 mutations located at the kinase solvent front site were identified as the major on-target mechanism of acquired resistance to both selpercatinib and pralsetinib. Several next-generation of RET TKIs capable of inhibiting the selpercatinib/pralsetinib-resistant RET mutants have progressed to clinical trials. However, it is likely that new TKI-adapted RET mutations will emerge to cause resistance to these next-generation of RET TKIs. Solving the problem requires a better understanding of the multiple mechanisms that support the RET TKI-tolerated persisters to identify a converging point of vulnerability to devise an effective co-treatment to eliminate the residual tumors.

RET蛋白是一种受体酪氨酸激酶。致癌RET融合或突变在非小细胞肺癌（NSCLC）和甲状腺癌中最为常见，在其他各类癌症中的发生率虽低，但呈现出不断上升的趋势。近年来，两种强效且具选择性的RET酪氨酸激酶抑制剂（TKIs）——普拉替尼（BLU - 667）和塞尔帕替尼（LOXO - 292、LY3527723）研发问世并获得监管部门批准。尽管普拉替尼和塞尔帕替尼的总缓解率（ORRs）较高，但实现完全缓解（CR）的患者比例不足10%。使用RET TKI治疗后，残余肿瘤不可避免地会产生耐药性，其原因包括二次靶基因突变、获得性替代癌基因以及MET扩增。位于激酶溶剂前沿位点的RET G810突变，已被确定为针对塞尔帕替尼和普拉替尼获得性耐药的主要靶向机制。目前，几种能够抑制对塞尔帕替尼/普拉替尼耐药的RET突变的下一代RET TKI，已进入临床试验阶段。然而，随着这些新药的使用，很可能会出现新的适应TKI的RET突变，从而导致肿瘤对这些下一代RET TKIs产生耐药性。要解决这一问题，需要更深入了解维持RET TKI耐药持久型细胞的多种机制，找出易受攻击的靶点，从而设计出有效的联合治疗方案来消除残余肿瘤。

原文信息

标题

Progress and challenges in RET-targeted cancer therapy

作者

Xueqing Hu, Ujjwol Khatri, Tao Shen, Jie Wu

机构

Peggy and Charles Stephenson Cancer Center, and Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA

通讯作者

Jie Wu