Targeting RAS phosphorylation in cancer therapy:Mechanisms and modulators  

作　　者：Yuran Qiu Yuanhao Wang Zongtao Chai Duan Ni Xinyi Li Jun Pu Jie Chen Jian Zhang Shaoyong Lu Chuan Lv Mingfei Ji 

机构地区：[1]Department of Urology,Changzheng Hospital,Naval Military Medical University,Shanghai 200003,China [2]Department of Pathophysiology,Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education,Shanghai Jiao Tong University,School of Medicine,Shanghai 200025,China [3]Department of Hepatic Surgery VI,Eastern Hepatobiliary Surgery Hospital,Second Military Medical University,Shanghai 200438,China [4]Department of Cardiology,Renji Hospital,Shanghai Jiao Tong University,School of Medicine,Shanghai 200120,China [5]Department of Plastic Surgery,Changhai Hospital,Naval Military Medical University,Shanghai 200438,China

出　　处：《Acta Pharmaceutica Sinica B》2021年第11期3433-3446,共14页药学学报（英文版）

基　　金：supported in part by grants from the National Natural Science Foundation of China(22077082,21778037,81925034,91753117,and 81721004);the Innovation Program of Shanghai Municipal Education Commission(2019-01-07-00-01E00036,China);the Shanghai Science and Technology Innovation(19431901600,China);the Shanghai Health and Family Planning System Excellent Subject Leader and Excellent Young Medical Talents Training Program(2018BR12,China)。

摘　　要：RAS,a member of the small GTPase family,functions as a binary switch by shifting between inactive GDP-loaded and active GTP-loaded state.RAS gain-of-function mutations are one of the leading causes in human oncogenesis,accounting for w19%of the global cancer burden.As a well-recognized target in malignancy,RAS has been intensively studied in the past decades.Despite the sustained efforts,many failures occurred in the earlier exploration and resulted in an‘undruggable’feature of RAS proteins.Phosphorylation at several residues has been recently determined as regulators for wild-type and mutated RAS proteins.Therefore,the development of RAS inhibitors directly targeting the RAS mutants or towards upstream regulatory kinases supplies a novel direction for tackling the anti-RAS difficulties.A better understanding of RAS phosphorylation can contribute to future therapeutic strategies.In this review,we comprehensively summarized the current advances in RAS phosphorylation and provided mechanistic insights into the signaling transduction of associated pathways.Importantly,the preclinical and clinical success in developing anti-RAS drugs targeting the upstream kinases and potential directions of harnessing allostery to target RAS phosphorylation sites were also discussed.

关 键 词：RAS PHOSPHORYLATION Undruggable Protein kinases ALLOSTERY 

分 类 号：R730.5[医药卫生—肿瘤]