Comprehensive analysis of metabolic isozyme targets in cancer

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• dc.contributor.author Marczyk, Michal
• dc.contributor.author Gunasekharan, Vignesh
• dc.contributor.author Casadevall Aguilar, David
• dc.contributor.author Qing, Tao
• dc.contributor.author Foldi, Julia
• dc.contributor.author Sehgal, Raghav
• dc.contributor.author Shan, Naing Lin
• dc.contributor.author Blenman, Kim R.M.
• dc.contributor.author O'Meara, Tess A.
• dc.contributor.author Umlauf, Sheila
• dc.contributor.author Surovtseva, Yulia V.
• dc.contributor.author Muthusamy, Viswanathan
• dc.contributor.author Rinehart, Jesse
• dc.contributor.author Perry, Rachel J.
• dc.contributor.author Kibbey, Richard
• dc.contributor.author Hatzis, Christos
• dc.contributor.author Pusztai, Lajos
• dc.date.accessioned 2022-11-03T07:08:19Z
• dc.date.issued 2022
• dc.description.abstract Metabolic reprogramming is a hallmark of malignant transformation, and loss of isozyme diversity (LID) contributes to this process. Isozymes are distinct proteins that catalyze the same enzymatic reaction but can have different kinetic characteristics, subcellular localization, and tissue specificity. Cancer-dominant isozymes that catalyze rate-limiting reactions in critical metabolic processes represent potential therapeutic targets. Here, we examined the isozyme expression patterns of 1,319 enzymatic reactions in 14 cancer types and their matching normal tissues using The Cancer Genome Atlas mRNA expression data to identify isozymes that become cancer-dominant. Of the reactions analyzed, 357 demonstrated LID in at least one cancer type. Assessment of the expression patterns in over 600 cell lines in the Cancer Cell Line Encyclopedia showed that these reactions reflect cellular changes instead of differences in tissue composition; 50% of the LID-affected isozymes showed cancer-dominant expression in the corresponding cell lines. The functional importance of the cancer-dominant isozymes was assessed in genome-wide CRISPR and RNAi loss-of-function screens: 17% were critical for cell proliferation, indicating their potential as therapeutic targets. Lists of prioritized novel metabolic targets were developed for 14 cancer types; the most broadly shared and functionally validated target was acetyl-CoA carboxylase 1 (ACC1). Small molecule inhibition of ACC reduced breast cancer viability in vitro and suppressed tumor growth in cell line- and patient-derived xenografts in vivo. Evaluation of the effects of drug treatment revealed significant metabolic and transcriptional perturbations. Overall, this systematic analysis of isozyme expression patterns elucidates an important aspect of cancer metabolic plasticity and reveals putative metabolic vulnerabilities.
• dc.format.mimetype application/pdf
• dc.identifier.citation Marczyk M, Gunasekharan V, Casadevall D, Qing T, Foldi J, Sehgal R, Shan NL, Blenman KRM, O'Meara TA, Umlauf S, Surovtseva YV, Muthusamy V, Rinehart J, Perry RJ, Kibbey R, Hatzis C, Pusztai L. Comprehensive analysis of metabolic isozyme targets in cancer. Cancer Res. 2022 May 3;82(9):1698-711. DOI: 10.1158/0008-5472.CAN-21-3983
• dc.identifier.doi http://dx.doi.org/10.1158/0008-5472.CAN-21-3983
• dc.identifier.issn 0008-5472
• dc.identifier.uri http://hdl.handle.net/10230/54662
• dc.language.iso eng
• dc.publisher American Association for Cancer Research (AACR)
• dc.relation.ispartof Cancer Res. 2022 May 3;82(9):1698-711
• dc.rights © American Association for Cancer Research (AACR) http://dx.doi.org/10.1158/0008-5472.CAN-21-3983
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.title Comprehensive analysis of metabolic isozyme targets in cancer
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/acceptedVersion