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

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.