Faculty, Staff and Student Publications

Publication Date

9-8-2023

Journal

Science

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.

Keywords

Humans, Endoribonucleases, Extracellular Signal-Regulated MAP Kinases, Neoplasms, Protein Serine-Threonine Kinases, Proteostasis, Proto-Oncogene Proteins p21(ras), Drug Resistance, Neoplasm, Enzyme Inhibitors, Antineoplastic Agents, Heat Shock Transcription Factors

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Associated Data

PMID: 37676964

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