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

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SCIENCE
卷 381, 期 6662, 页码 1065-+

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AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.abn4180

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Proteostasis reprogramming is identified as a key convergence point of multiple mechanisms of resistance to mutant KRAS inhibitors. The reactivation of IRE1a, in an ER stress-independent manner, restores proteostasis in acquired KRAS inhibitor-resistant tumors. IRE1a phosphorylation and stability are promoted by reactivated ERK and hyperactivated AKT, which can be overcome by suppressing IRE1a.
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.

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