Modulation of the proteostasis network promotes tumor resistance to oncogenic KRAS inhibitors
Xiangdong Lv, Xuan Lu, Jin Cao, Qin Luo, Yao Ding, Fanglue Peng, Apar Pataer, Dong Lu, Dong Han, Eric Malmberg, Doug W. Chan, Xiaoran Wang, Sara R. Savage, Sufeng Mao, Jingjing Yu, Fei Peng, Yan Liang, Huan Meng, Laure Maneix, Han Yu-min, Yiwen Chen, Wantong Yao, Eric C. Chang, André Catic, Xia Lin, George Miles, Pengxiang Huang, Zheng Sun, Bryan M. Burt, Huamin Wang, Jin Wang, Qizhi Yao, Bing Zhang, Jack A. Roth, Bert W. O’Malley, Matthew J. Ellis, Mothaffar F. Rimawi, Haoqiang Ying, Xi Chen
Abstract
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 1α (IRE1α) branch of the unfolded protein response, causing severe proteostasis disturbances. However, IRE1α was selectively reactivated in an ER stress-independent manner in acquired KRASi-resistant tumors, restoring proteostasis. Oncogenic KRAS promoted IRE1α protein stability through extracellular signal-regulated kinase (ERK)-dependent phosphorylation of IRE1α, leading to IRE1α disassociation from 3-hydroxy-3-methylglutaryl reductase degradation (HRD1) E3-ligase. In KRASi-resistant tumors, both reactivated ERK and hyperactivated AKT restored IRE1α phosphorylation and stability. Suppression of IRE1α overcame resistance to KRASi. This study reveals a druggable mechanism that leads to proteostasis reprogramming and facilitates KRASi resistance.