Metabolism-focused CRISPR screen unveils mitochondrial pyruvate carrier 1 as a critical driver for PARP inhibitor resistance in lung cancer.

Autor: Furusawa T; Developmental Therapeutics Branch, NCI Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States., Cavero R; Developmental Therapeutics Branch, NCI Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States., Liu Y; Department of Molecular Biosciences, The University of Texas at Austin, Austin, Texas, USA., Li H; Developmental Therapeutics Branch, NCI Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States.; Department of Molecular Biosciences, The University of Texas at Austin, Austin, Texas, USA., Xu X; Protein Characterization Laboratory, Frederick National Laboratory for Cancer Research, Cancer Research Technology Program, Leidos Biomedical Research Inc., Frederick, Maryland, USA., Andresson T; Protein Characterization Laboratory, Frederick National Laboratory for Cancer Research, Cancer Research Technology Program, Leidos Biomedical Research Inc., Frederick, Maryland, USA., Reinhold W; Developmental Therapeutics Branch, NCI Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States., White O; Surgical Oncology Program, NCI Center for Cancer Research, NCI, NIH., Bethesda, Maryland, United States., Boufraqech M; Surgical Oncology Program, NCI Center for Cancer Research, NCI, NIH., Bethesda, Maryland, United States., Meyer TJ; CCR Collaborative Bioinformatics Resource (CCBR), Leidos Biomedical Research Inc., Frederick, Maryland, USA., Hartmann O; Institute of Lung Health and Immunity, Helmholtz Center, Munich, Germany.; German Center for Lung Research, DZL, Giessen, Germany.; Helmholtz Center Munich, Munich, Germany., Diefenbacher ME; Institute of Lung Health and Immunity, Helmholtz Center, Munich, Germany.; German Center for Lung Research, DZL, Giessen, Germany.; Helmholtz Center Munich, Munich, Germany., Pommier Y; Developmental Therapeutics Branch, NCI Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States., Weyemi U; Developmental Therapeutics Branch, NCI Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States.
Jazyk: angličtina
Zdroj: Molecular carcinogenesis [Mol Carcinog] 2024 Jun; Vol. 63 (6), pp. 1024-1037. Date of Electronic Publication: 2024 Feb 27.
DOI: 10.1002/mc.23705
Abstrakt: Homologous recombination (HR) and poly ADP-ribosylation are partially redundant pathways for the repair of DNA damage in normal and cancer cells. In cell lines that are deficient in HR, inhibition of poly (ADP-ribose) polymerase (poly (ADP-ribose) polymerase [PARP]1/2) is a proven target with several PARP inhibitors (PARPis) currently in clinical use. Resistance to PARPi often develops, usually involving genetic alterations in DNA repair signaling cascades, but also metabolic rewiring particularly in HR-proficient cells. We surmised that alterations in metabolic pathways by cancer drugs such as Olaparib might be involved in the development of resistance to drug therapy. To test this hypothesis, we conducted a metabolism-focused clustered regularly interspaced short palindromic repeats knockout screen to identify genes that undergo alterations during the treatment of tumor cells with PARPis. Of about 3000 genes in the screen, our data revealed that mitochondrial pyruvate carrier 1 (MPC1) is an essential factor in desensitizing nonsmall cell lung cancer (NSCLC) lung cancer lines to PARP inhibition. In contrast to NSCLC lung cancer cells, triple-negative breast cancer cells do not exhibit such desensitization following MPC1 loss and reprogram the tricarboxylic acid cycle and oxidative phosphorylation pathways to overcome PARPi treatment. Our findings unveil a previously unknown synergistic response between MPC1 loss and PARP inhibition in lung cancer cells.
(© 2024 The Authors. Molecular Carcinogenesis published by Wiley Periodicals LLC.)
Databáze: MEDLINE
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