Progress and challenges in RET-targeted cancer therapy

作     者：Xueqing Hu Ujjwol Khatri Tao Shen Jie Wu Xueqing Hu;Ujjwol Khatri;Tao Shen;Jie Wu

作者机构：Peggy and Charles Stephenson Cancer Centerand Department of PathologyUniversity of Oklahoma Health Sciences CenterOklahoma CityOK 73104USA 

出 版 物：《Frontiers of Medicine》 (医学前沿（英文版）)

年 卷 期：2023年第17卷第2期

页      面：207-219页

核心收录：

学科分类：1002[医学-临床医学] 100214[医学-肿瘤学] 10[医学] 

基　　金：Cancer research in Jie Wu’s laboratory was supported by NIH grants R01CA242845,R01CA273168,a PHF SEED grant Oklahoma Center for the Advancement of Science and Technology(OCAST)grant HR19-026 Additional support was provided by the Oklahoma Tobacco Settlement Endowment Trust,and the Peggy and Charles Stephenson Endowment,and NIH grants P30CA225520 and P20GM103639 to the institution 

主　　题：pralsetinib selpercatinib RET-alteration lung cancer thyroid cancer tumor-agnostic therapy drug resistance 

摘      要：The rearranged during transfection(RET)is a receptor protein tyrosine *** 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 *** 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 *** 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 *** G810 mutations located at the kinase solvent front site were identified as the major on-target mechanism of acquired resistance to both selpercatinib and *** next-generation of RET TKIs capable of inhibiting the selpercatinib/pralsetinib-resistant RET mutants have progressed to clinical ***,it is likely that new TKI-adapted RET mutations will emerge to cause resistance to these next-generation of RET *** 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.