Targeting RAF dimers in RAS mutant tumors:From biology to clinic  

作　　者：Huanhuan Yin Qiulin Tang Hongwei Xia Feng Bi 

机构地区：[1]Division of Abdominal Cancer,Department of Medical Oncology,Cancer Center and Laboratory of Molecular Targeted Therapy in Oncology,West China Hospital,Sichuan University,Chengdu 610041,China

出　　处：《Acta Pharmaceutica Sinica B》2024年第5期1895-1923,共29页药学学报（英文版）

基　　金：This study was supported by the National Natural Science Foundation of China(82073059,82073314);the Sichuan Science and Technology Program(2023NSFSC1838,China);the Sichuan University Postdoctoral Interdisciplinary Innovation Fund(JCXK2212,China).

摘　　要：RAS mutations occur in approximately 30%of tumors worldwide and have a poor prognosis due to limited therapies.Covalent targeting of KRAS G12C has achieved significant success in recent years,but there is still a lack of efficient therapeutic approaches for tumors with non-G12C KRAS mutations.A highly promising approach is to target the MAPK pathway downstream of RAS,with a particular focus on RAF kinases.First-generation RAF inhibitors have been authorized to treat BRAF mutant tumors for over a decade.However,their use in RAS-mutated tumors is not recommended due to the paradoxical ERK activation mainly caused by RAF dimerization.To address the issue of RAF dimerization,type II RAF inhibitors have emerged as leading candidates.Recent clinical studies have shown the initial effectiveness of these agents against RAS mutant tumors.Promisingly,type II RAF inhibitors in combination with MEK or ERK inhibitors have demonstrated impressive efficacy in RAS mutant tumors.This review aims to clarify the importance of RAF dimerization in cellular signaling and resistance to treatment in tumors with RAS mutations,as well as recent progress in therapeutic approaches to address the problem of RAF dimerization in RAS mutant tumors.

关 键 词：RAS mutations RAF dimerization RAF inhibitors Cancer therapy Drug resistance 

分 类 号：R730.5[医药卫生—肿瘤]