ArticleScience (New York, N.Y.)2023
Modulation of the proteostasis network promotes tumor resistance to oncogenic KRAS inhibitors.
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Article in Science (New York, N.Y.), 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 80 papers.
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80citing papers in PubMed
15.1field-weighted citation impact, top 1% of its field
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Who cites it
80 citing papers in PubMed, 98 citations in OpenAlex.
- Chromosomal instability in cancer: sources, consequences and new therapeutic opportunities.Signal transduction and targeted therapy · 2026Review
- Drug repurposing in KRAS G12C-mutant NSCLC: a focus on resistance mechanisms and clinical strategies.Naunyn-Schmiedeberg's archives of pharmacology · 2026Review
- Tumor microenvironment and signaling pathways in melanoma brain metastasis.Annals of translational medicine · 2026Review
- Article
- CDK8 remodels the tumor microenvironment and promotes resistance to KRASThe EMBO journal · 2026Article
- Oncogenic Kras targeting with MRTX1133 or Daraxonrasib specifically synergize with anti-CTLA4 to promote anti-tumor immunity in pancreatic cancer.Nature communications · 2026Article
- CAF-derived PAI-1 serves as an EGFR ligand and fuels KRAS-mutant pancreatic cancer.Nature communications · 2026Article
- Article
- The role of the WD40-repeat protein family in cancer.Molecular cancer · 2026Review
- Targeting WFS1 overcomes KRASNPJ precision oncology · 2026Article
- Hallmarks of the ageing lung: 10 years later.The European respiratory journal · 2026Review
- Expression of LIFR in tumor and SHOC2, YAP1 in plasma mRNA as potential biomarkers in KRASScientific reports · 2026Article
- Ratiometric transcriptional activation by protein degradation.bioRxiv : the preprint server for biology · 2026Article
- Article
- Targeting the IRE1α-XBP1 signaling axis impairs tumor growth and promotes myogenic differentiation in rhabdomyosarcoma.Communications biology · 2026Article
- Targeting ubiquitin signaling vulnerabilities in KEAP1-inactivated lung cancer.The EMBO journal · 2026Article
- Chemotherapy in combination with KRAS inhibitors inJournal of thoracic disease · 2026Article
- Targeting the TRIM25-AGO2-miR-148b-5p-ABCC1 axis overcomes chemoresistance in non-small cell lung cancer.Cell death & disease · 2026Article
- Targeting the IRE1α-XBP1 signaling axis impairs tumor growth and promotes myogenic differentiation in rhabdomyosarcoma.bioRxiv : the preprint server for biology · 2026Article
- Article
20 more citing papers are in PubMed but not listed here.
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Authors and funding
39 authors at 2 institutions in 2 countries.
Xiangdong Lv *Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.ORCID 0000-0001-5310-5816
Xuan Lu *Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.ORCID 0000-0003-3716-3017
Jin Cao *Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.ORCID 0000-0002-0456-5696
Qin LuoDepartment of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
Yao DingDepartment of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
Fanglue PengDepartment of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.ORCID 0000-0001-8818-3785
Apar PataerDepartment of Thoracic and Cardiovascular Surgery, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.ORCID 0000-0002-1960-3579
Dong LuDepartment of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.ORCID 0000-0002-9919-6378
Dong HanDepartment of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.ORCID 0000-0003-4009-8172
Eric MalmbergDepartment of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.ORCID 0000-0002-6279-3590
Doug W ChanDepartment of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.ORCID 0000-0002-6986-5497
Xiaoran WangDepartment of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.ORCID 0000-0003-4827-6930
Sara R SavageLester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA.ORCID 0000-0002-8170-3132
Sufeng MaoDepartment of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.ORCID 0009-0006-0744-5282
Jingjing YuDepartment of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
Fei PengDepartment of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.ORCID 0000-0002-5446-9854
Liang YanDepartment of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.ORCID 0000-0002-3002-5431
Huan MengDepartment of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.ORCID 0000-0001-6698-7918
Laure ManeixDepartment of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.ORCID 0000-0003-0044-5395
Yumin HanDepartment of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
Yiwen ChenDepartment of Bioinformatics and Computational Biology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.ORCID 0000-0002-7706-7540
Wantong YaoDepartment of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Eric C ChangDepartment of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.ORCID 0000-0002-1375-5088
Andre CaticDepartment of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.ORCID 0000-0002-3572-7598
Xia LinDivision of Surgical Oncology, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX 77030, USA.
George MilesLester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA.
Pengxiang HuangDepartment of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
Zheng SunDepartment of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.ORCID 0000-0002-6858-0633
Bryan BurtDivision of Thoracic Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX 77030, USA.
Huamin WangDepartment of Pathology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Jin WangDepartment of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.ORCID 0000-0003-3625-7919
Qizhi Cathy YaoDivision of Surgical Oncology, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX 77030, USA.ORCID 0000-0002-2267-0588
Bing ZhangLester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA.ORCID 0000-0001-8676-2425
Jack A RothDepartment of Thoracic and Cardiovascular Surgery, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.ORCID 0000-0002-8955-1313
Bert W O'MalleyDepartment of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.ORCID 0000-0003-3332-1399
Matthew J EllisLester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA.ORCID 0000-0002-8467-8534
Mothaffar F RimawiLester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA.ORCID 0000-0002-4284-5656
Haoqiang YingDepartment of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.ORCID 0000-0003-0616-2310
Xi ChenDepartment of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.ORCID 0000-0002-7995-6202
Baylor College of Medicine · USThe University of Texas MD Anderson Cancer Center · US
Funding
Tumor BiologyP30CA125123 · NCI · BAYLOR COLLEGE OF MEDICINE · PI Michael M Ittmann · 2007 to 2026
$73.9MTissue ResourceP50CA126752 · NCI · BAYLOR COLLEGE OF MEDICINE · PI Leonid S Metelitsa · 2007 to 2026
$51.4MThe RAS and P13K Pathways in Pancreatic AdenocarcinomaP01CA117969 · NCI · UNIVERSITY OF TX MD ANDERSON CAN CTR · PI DEPINHO, RONALD ANTHONY · 2006 to 2025
$41.7MTissue Analysis & Molecular Imaging CoreP30DK056338 · NIDDK · BAYLOR COLLEGE OF MEDICINE · PI James Versalovic · 2001 to 2026
$28.3MTranslational Research in Breast Cancer (SPORE)P50CA186784 · NCI · BAYLOR COLLEGE OF MEDICINE · PI MATTHEW J ELLIS · 2014 to 2026
$24.5MREPRODUCTIVE HORMONES: BIOLOGICAL AND MOLECULAR ACTIONSR01HD008188 · NICHD · BAYLOR COLLEGE OF MEDICINE · PI DAVID M LONARD, JOHN P LYDON · 1985 to 2026
$16.3MSEX HORMONE RECEPTOR COMPONENTS AND THE CELL GENOMER01HD007857 · NICHD · BAYLOR COLLEGE OF MEDICINE · PI DAVID M LONARD, JOHN P LYDON · 1985 to 2026
$14.6MUCSF Project 1U54CA224081 · NCI · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI Trever G Bivona, Jack Roth · 2017 to 2026
$12.9MHematology Training ProgramT32DK060445 · NIDDK · BAYLOR COLLEGE OF MEDICINE · PI GOODELL, MARGARET A. · 2002 to 2023
$8.3MUniversity of Texas PDX Development and Trial CenterU54CA224065 · NCI · UNIVERSITY OF TX MD ANDERSON CAN CTR · PI MERIC-BERNSTAM, FUNDA, ROTH, JACK · 2017 to 2022
$7.7MiPGDAC, An Integrative Proteogenomic Data Analysis Center for CPTACU24CA210954 · NCI · BAYLOR COLLEGE OF MEDICINE · PI ZHANG, BING · 2016 to 2020
$4.9MProteomic determinants of response to checkpoint blockade in malignant pleuralmesotheliomaR37CA248478 · NCI · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI Bryan Michael Burt · 2021 to 2026
$2.9MNCI NIH HHS P01 CA117969NCI NIH HHS P30 CA125123NCI NIH HHS P50 CA126752NCI NIH HHS P50 CA186784NCI NIH HHS R01 CA195651NCI NIH HHS R01 CA196941NCI NIH HHS R01 CA214793NCI NIH HHS R01 CA270240NCI NIH HHS R21 CA215591NCI NIH HHS R37 CA228304NCI NIH HHS R37 CA248478NCI NIH HHS R37 CA272744NCI NIH HHS U24 CA210954NCI NIH HHS U54 CA224065NCI NIH HHS U54 CA224081NCRR NIH HHS S10 RR024574NHLBI NIH HHS R01 HL146642NICHD NIH HHS R01 HD007857NICHD NIH HHS R01 HD008188NICHD NIH HHS R01 HD100535NIDDK NIH HHS P30 DK056338NIDDK NIH HHS R01 DK115454NIDDK NIH HHS T32 DK060445NIGMS NIH HHS R01 GM130838NIGMS NIH HHS R01 GM142143NIH HHS S10 OD025251NIH HHS S10 OD028671NINDS NIH HHS R01 NS117668
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.
Indexed as
Antineoplastic AgentsDrug Resistance, NeoplasmEndoribonucleasesEnzyme InhibitorsExtracellular Signal-Regulated MAP KinasesHeat Shock Transcription FactorsNeoplasmsProteostasisProto-Oncogene Proteins p21(ras)HumansProtein Serine-Threonine KinasesAntineoplastic AgentsEndoribonucleasesEnzyme InhibitorsERN1 protein, humanExtracellular Signal-Regulated MAP KinasesHeat Shock Transcription FactorsHSF1 protein, humanKRAS protein, humanProtein Serine-Threonine KinasesProto-Oncogene Proteins p21(ras)
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