{"doi":"10.1126/science.abn4180","title":"Modulation of the proteostasis network promotes tumor resistance to oncogenic KRAS inhibitors","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.","journal":"Science","year":2023,"id":316178,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":113,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9582,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1019533,"name":"Xuan Lu","orcid":"0000-0003-3716-3017","position":1,"is_corresponding":false},{"id":277748,"name":"Jin Cao","orcid":"0000-0002-0456-5696","position":2,"is_corresponding":false},{"id":416516,"name":"Qin Luo","orcid":"0000-0002-1351-7231","position":3,"is_corresponding":false},{"id":345632,"name":"Yao Ding","orcid":"0000-0002-0559-5846","position":4,"is_corresponding":false},{"id":311913,"name":"Fanglue Peng","orcid":"0000-0001-8818-3785","position":5,"is_corresponding":false},{"id":274143,"name":"Apar Pataer","orcid":"0000-0002-1960-3579","position":6,"is_corresponding":false},{"id":245724,"name":"Dong Lu","orcid":"0000-0002-9919-6378","position":7,"is_corresponding":false},{"id":867259,"name":"Dong Han","orcid":"0000-0003-4009-8172","position":8,"is_corresponding":false},{"id":241896,"name":"Eric Malmberg","orcid":"0000-0002-6279-3590","position":9,"is_corresponding":false},{"id":270272,"name":"Doug W. 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