Decoding the proteostasis network in resistance to KRAS inhibitors

作     者：Xinxin Song Zhuan Zhou Kenneth D.Westover 

作者机构：Department of SurgeryUniversity of Texas Southwestern Medical CenterDallasTX 75390USA Departments of Radiation Oncology and BiochemistryUniversity of Texas Southwestern Medical CenterDallasTX 75390USA 

出 版 物：《The Innovation》 (创新（英文）)

年 卷 期：2023年第4卷第6期

页      面：7-8页

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

基　　金：We thank Dave Primm(Department of Surgery,University of Texas Southwestern Med-ical Center)for his critical reading of the manuscript.X.S.was supported by an American Cancer Society grant(RG-21-142-16) National Institutes of Health grant(P30CA142543) Simmons Comprehensive Cancer Center and is supported by a startup fund bythe Department of Surgery at the University of Texas Southwestem Medical Center.K.D.W.is supported by grants from the National Institutes of Health(R01 CA244341) Cancer Prevention and Research Institute of Texas(RP220145) 

主　　题：KRAS resistance network 

摘      要：The Kirsten rat sarcoma(KRAS)gene,which is one of the most frequently mutated genes in human cancers,has long captured the attention of *** recent approval of KRAS G12C inhibitors(KRASi),such as sotorasib and adagrasib,has signaled a promising turn in cancer ***,emerging resistance to these drugs presents a fomidable challenge. Lv et al s2 publication in Science suggests that the proteostasis network plays a role in mediating diverse KRASi resistance *** work shows that KRAS inhibition suppresses protein quality control in the majority of cancer *** the remaining cells,a subset can reactivate one of the endoplasmic reticulum(ER)stress sensors,specifically the inositol-requiring enzyme 1 alpha(IRE1a)branch of the unfolded protein response(UPR).This adaptation enables the cells to overcome their reliance on oncogenic KRAS,enhancing their resistance to KRASi(Figure 1).This insight underscores the complex interplay be tween oncogenic signaling and protein quality control in scenarios of drug ***,we review and discuss the major findings of this study in the following sections.