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

Autor: Lv X; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.; Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA.; Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA., Lu X; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.; Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA.; Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA., Cao J; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.; Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA.; Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA., Luo Q; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.; Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA.; Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA., Ding Y; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.; Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA.; Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA., Peng F; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.; Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA.; Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA., Pataer A; Department of Thoracic and Cardiovascular Surgery, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA., Lu D; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.; Department of Pharmacology and Chemical Biology, Baylor College of Medicine, Houston, TX 77030, USA.; Center for Drug Discovery, Baylor College of Medicine, Houston, TX 77030, USA., Han D; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.; Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA.; Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA., Malmberg E; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.; Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA.; Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA., Chan DW; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.; Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA.; Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA., Wang X; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.; Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA.; Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA., Savage SR; Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA.; Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA.; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA., Mao S; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.; Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA.; Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA., Yu J; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.; Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA.; Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA., Peng F; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.; Department of Medicine, Division of Diabetes, Endocrinology and Metabolism, Baylor College of Medicine, Houston, TX 77030, USA., Yan L; Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA., Meng H; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA., Maneix L; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.; Huffington Center on Aging, Baylor College of Medicine, USA., Han Y; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.; Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA.; Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA., Chen Y; Department of Bioinformatics and Computational Biology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA., Yao W; Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA., Chang EC; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.; Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA.; Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA., Catic A; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.; Huffington Center on Aging, Baylor College of Medicine, USA., Lin X; Division of Surgical Oncology, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX 77030, USA., Miles G; Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA.; Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA.; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA., Huang P; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA., Sun Z; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.; Department of Medicine, Division of Diabetes, Endocrinology and Metabolism, Baylor College of Medicine, Houston, TX 77030, USA., Burt B; Division of Thoracic Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX 77030, USA., Wang H; Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA., Wang J; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.; Department of Pharmacology and Chemical Biology, Baylor College of Medicine, Houston, TX 77030, USA.; Center for Drug Discovery, Baylor College of Medicine, Houston, TX 77030, USA., Yao QC; Division of Surgical Oncology, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX 77030, USA., Zhang B; Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA.; Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA.; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA., Roth JA; Department of Thoracic and Cardiovascular Surgery, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA., O'Malley BW; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA., Ellis MJ; Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA.; Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA.; Early Oncology, Oncology R&D, AstraZeneca, Gaithersburg, MD, USA., Rimawi MF; Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA.; Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA., Ying H; Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA., Chen X; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.; Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA.; Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA.
Jazyk: angličtina
Zdroj: Science (New York, N.Y.) [Science] 2023 Sep 08; Vol. 381 (6662), pp. eabn4180. Date of Electronic Publication: 2023 Sep 08.
DOI: 10.1126/science.abn4180
Abstrakt: 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.
Databáze: MEDLINE
Nepřihlášeným uživatelům se plný text nezobrazuje