Mutant KRAS as a critical determinant of the therapeutic response of colorectal cancer

作     者：Kyle Knickelbein Lin Zhang 

作者机构：University of Pittsburgh Cancer InstituteDepartments of Pharmacology&Chemical BiologyUniversity of Pittsburgh School of MedicinePittsburghPA 15213USA 

出 版 物：《Genes & Diseases》 (基因与疾病（英文）)

年 卷 期：2015年第2卷第1期

页      面：4-12页

学科分类：0710[理学-生物学] 0831[工学-生物医学工程（可授工学、理学、医学学位）] 1002[医学-临床医学] 1001[医学-基础医学(可授医学、理学学位)] 100214[医学-肿瘤学] 0703[理学-化学] 10[医学] 

基　　金：supported in part by the graduate student fellowship from the Department of Pharmacology&Chemical Biology Research in L.Z.’s lab is supported by the National Institute of Health grants R01CA106348 and R01CA172136. 

主　　题：Colorectal cancer EGFR KRAS Synthetic lethality Targeted therapy 

摘      要：Mutations in the KRAS oncogene represent one of the most prevalent genetic alterations in colorectal cancer(CRC),the third leading cause of cancer-related death in the US.In addition to their well-characterized function in driving tumor progression,KRAS mutations have been recognized as a critical determinant of the therapeutic response of CRC.Recent studies demonstrate that KRAS-mutant tumors are intrinsically insensitive to clinically-used epidermal growth factor receptor(EGFR)targeting antibodies,including cetuximab and panitumumab.Acquired resistance to the anti-EGFR therapy was found to be associated with enrichment of KRAS-mutant tumor cells.However,the underlying molecular mechanism of mutant-KRAS-mediated therapeutic resistance has remained unclear.Despite intensive efforts,directly targeting mutant KRAS has been largely unsuccessful.This review summarizes the recent advances in understanding the biological function of KRAS mutations in determining the therapeutic response of CRC,highlighting several recently developed agents and strategies for targeting mutant KRAS,such as synthetic lethal interactions.