دورية أكاديمية
أعرض في EDS

Targeting the mevalonate pathway suppresses ARID1A-inactivated cancers by promoting pyroptosis.

التفاصيل البيبلوغرافية
العنوان: Targeting the mevalonate pathway suppresses ARID1A-inactivated cancers by promoting pyroptosis.
المؤلفون: Zhou W; Immunology, Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA 19104, USA., Liu H; Immunology, Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA 19104, USA., Yuan Z; Immunology, Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA 19104, USA., Zundell J; Immunology, Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA 19104, USA., Towers M; Department of Experimental Therapeutics, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA., Lin J; Immunology, Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA 19104, USA., Lombardi S; Immunology, Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA 19104, USA; Department of Pharmacy and Biotechnology, University of Bologna, 40126, Bologna, Italy., Nie H; Immunology, Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA 19104, USA., Murphy B; Immunology, Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA 19104, USA., Yang T; Immunology, Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA 19104, USA., Wang C; Immunology, Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA 19104, USA., Liao L; Immunology, Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA 19104, USA., Goldman AR; Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, PA 19104, USA., Kannan T; Bioinformatics Facility, The Wistar Institute, Philadelphia, PA 19104, USA., Kossenkov AV; Gene Expression and Regulation Program, The Wistar Institute, Philadelphia, PA 19104, USA., Drapkin R; Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Obstetrics and Gynecology, Penn Ovarian Cancer Research Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA., Montaner LJ; Immunology, Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA 19104, USA., Claiborne DT; Immunology, Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA 19104, USA., Zhang N; Immunology, Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA 19104, USA., Wu S; Immunology, Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA 19104, USA., Zhang R; Immunology, Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA 19104, USA; Department of Experimental Therapeutics, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA. Electronic address: rzhang11@mdanderson.org.
المصدر: Cancer cell [Cancer Cell] 2023 Apr 10; Vol. 41 (4), pp. 740-756.e10. Date of Electronic Publication: 2023 Mar 23.
نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't; Research Support, N.I.H., Extramural; Research Support, U.S. Gov't, Non-P.H.S.
اللغة: English
بيانات الدورية: Publisher: Cell Press Country of Publication: United States NLM ID: 101130617 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1878-3686 (Electronic) Linking ISSN: 15356108 NLM ISO Abbreviation: Cancer Cell Subsets: MEDLINE
أسماء مطبوعة: Original Publication: Cambridge, Mass. : Cell Press, c2002-
مواضيع طبية MeSH: Ovarian Neoplasms*/drug therapy , Ovarian Neoplasms*/genetics , Ovarian Neoplasms*/metabolism , Carcinoma*, Humans ; Female ; Mice ; Animals ; Mevalonic Acid ; Pyroptosis ; Nuclear Proteins/genetics ; Mutation ; DNA-Binding Proteins/genetics ; Transcription Factors/genetics
مستخلص: ARID1A, encoding a subunit of the SWI/SNF complex, is mutated in ∼50% of clear cell ovarian carcinoma (OCCC) cases. Here we show that inhibition of the mevalonate pathway synergizes with immune checkpoint blockade (ICB) by driving inflammasome-regulated immunomodulating pyroptosis in ARID1A-inactivated OCCCs. SWI/SNF inactivation downregulates the rate-limiting enzymes in the mevalonate pathway such as HMGCR and HMGCS1, which creates a dependence on the residual activity of the pathway in ARID1A-inactivated cells. Inhibitors of the mevalonate pathway such as simvastatin suppresses the growth of ARID1A mutant, but not wild-type, OCCCs. In addition, simvastatin synergizes with anti-PD-L1 antibody in a genetic OCCC mouse model driven by conditional Arid1a inactivation and in a humanized immunocompetent ARID1A mutant patient-derived OCCC mouse model. Our data indicate that inhibition of the mevalonate pathway simultaneously suppresses tumor cell growth and boosts antitumor immunity by promoting pyroptosis, which synergizes with ICB in suppressing ARID1A-mutated cancers.
Competing Interests: Declaration of interests The authors declare no competing interests.
(Copyright © 2023 Elsevier Inc. All rights reserved.)
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معلومات مُعتمدة: P30 CA016672 United States CA NCI NIH HHS; R01 CA165065 United States CA NCI NIH HHS; P30 CA010815 United States CA NCI NIH HHS; P50 CA228991 United States CA NCI NIH HHS; R50 CA211199 United States CA NCI NIH HHS; R01 CA202919 United States CA NCI NIH HHS; R01 CA239128 United States CA NCI NIH HHS; R01 CA260661 United States CA NCI NIH HHS; T32 CA009171 United States CA NCI NIH HHS; R01 CA163377 United States CA NCI NIH HHS
فهرسة مساهمة: Keywords: ARID1A; Pyroptosis; SWI/SNF; anti-PD-L1; humanized mouse model; immune checkpoint blockade; inflammasome; mevalonate pathway; ovarian cancer; statin
المشرفين على المادة: S5UOB36OCZ (Mevalonic Acid)
0 (Nuclear Proteins)
0 (ARID1A protein, human)
0 (DNA-Binding Proteins)
0 (Transcription Factors)
0 (Arid1a protein, mouse)
تواريخ الأحداث: Date Created: 20230324 Date Completed: 20230412 Latest Revision: 20240515
رمز التحديث: 20240515
مُعرف محوري في PubMed: PMC10085864
DOI: 10.1016/j.ccell.2023.03.002
PMID: 36963401
قاعدة البيانات: MEDLINE
الوصف
تدمد:1878-3686
DOI:10.1016/j.ccell.2023.03.002