Modulation of the proteostasis network promotes tumor resistance to oncogenic KRAS inhibitors

• 成果类型: Article
• 署名作者: Lv, Xiangdong; Lu, Xuan; Cao, Jin; Luo, Qin; Ding, Yao; Peng, Fanglue; Pataer, Apar; Lu, Dong; Han, Dong; Malmberg, Eric; Chan, Doug W.; Wang, Xiaoran; Savage, Sara R.; Mao, Sufeng; Yu, Jingjing; Peng, Fei; Yan, Liang; Meng, Huan; Maneix, Laure; Han, Yumin; Chen, Yiwen; Yao, Wantong; Chang, Eric C.; Catic, Andre; Lin, Xia; Miles, George; Huang, Pengxiang; Sun, Zheng; Burt, Bryan; Wang, Huamin; Wang, Jin; Yao, Qizhi Cathy; Zhang, Bing; Roth, Jack A.; O'Malley, Bert W.; Ellis, Matthew J.; Rimawi, Mothaffar F.; Ying, Haoqiang; Chen, Xi
• 署名单位: Baylor College of Medicine; Baylor College of Medicine; Baylor College of Medicine; University of Texas System; UTMD Anderson Cancer Center; Baylor College of Medicine; Baylor College of Medicine; Baylor College of Medicine; Baylor College of Medicine; University of Texas System; UTMD Anderson Cancer Center; Baylor College of Medicine; University of Texas System; UTMD Anderson Cancer Center; University of Texas System; UTMD Anderson Cancer Center; Baylor College of Medicine; Baylor College of Medicine; University of Texas System; UTMD Anderson Cancer Center; AstraZeneca
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-14079
• DOI: 10.1126/science.abn4180
• 发表日期: 2023-09-08
• 页码: 1065-+
• 关键词: endoplasmic-reticulum; pancreatic-cancer; transmembrane protein; messenger-rna; aaa-atpase; er stress; ras; ire1; PATHWAY; activation

摘要

Despite substantial advances in targeting mutant KRAS, tumor resistance to KRAS inhibitors (KRASi) remains a major barrier to progress. Here, we report proteostasis reprogramming as a key convergence point of multiple KRASi-resistance mechanisms. Inactivation of oncogenic KRAS down-regulated both the heat shock response and the inositol-requiring enzyme 1a (IRE1a) branch of the unfolded protein response, causing severe proteostasis disturbances. However, IRE1a was selectively reactivated in an ER stress-independent manner in acquired KRASi-resistant tumors, restoring proteostasis. Oncogenic KRAS promoted IRE1a protein stability through extracellular signal-regulated kinase (ERK)-dependent phosphorylation of IRE1a, leading to IRE1a disassociation from 3-hydroxy-3-methylglutaryl reductase degradation (HRD1) E3-ligase. In KRASi-resistant tumors, both reactivated ERK and hyperactivated AKT restored IRE1a phosphorylation and stability. Suppression of IRE1a overcame resistance to KRASi. This study reveals a druggable mechanism that leads to proteostasis reprogramming and facilitates KRASi resistance.