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

• Published in: Science (American Association for the Advancement of Science) 2023-09, Vol.381 (6662), p.eabn4180-eabn4180
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: Addictions; AKT protein; Antineoplastic Agents - pharmacology; Cancer; Convergence; Crosstalk; Deactivation; Drug Resistance, Neoplasm; Endoplasmic reticulum; Endoribonucleases; Enzyme Inhibitors - pharmacology; Extracellular signal-regulated kinase; Extracellular Signal-Regulated MAP Kinases; Heat shock; Heat shock factors; Heat Shock Transcription Factors - metabolism; Homeostasis; HSF1 protein; Humans; Inactivation; Inhibition; Inhibitors; Inositol; Inositols; K-Ras protein; Kinases; Lung cancer; MAP kinase; Mutants; Neoplasms - drug therapy; Neoplasms - genetics; Networks; Non-small cell lung carcinoma; Oncogenes; Patients; Pharmacology; Phosphorylation; Protein Serine-Threonine Kinases; Proteins; Proteostasis; Proto-Oncogene Proteins p21(ras) - antagonists & inhibitors; Proto-Oncogene Proteins p21(ras) - genetics; Quality control; Signal transduction; Small cell lung carcinoma; Stability; Survival; Target acquisition; Toxicity; Tumors; Tyrosine; Ubiquitin-protein ligase; Ubiquitination
• ISSN: 0036-8075; 1095-9203; 1095-9203
• DOI: 10.1126/science.abn4180

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.