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Integrated Metabolic Profiling and Gene Expression Analysis Reveals Therapeutic Modalities in Breast Cancer

ABSTRACT: Integrated Metabolic Profiling and Gene Expression Analysis Reveals Therapeutic Modalities in Breast Cancer

PROVIDER: PRJNA720181 | ENA |

REPOSITORIES: ENA

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Integrated Metabolic Profiling and Gene Expression Analysis Reveals Therapeutic Modalities in Breast Cancer

Project description:Integrated Metabolic Profiling and Gene Expression Analysis Reveals Therapeutic Modalities in Breast Cancer

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Integrated Metabolic Profiling and Gene Expression Analysis Reveals Therapeutic Modalities in Breast Cancer

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Integrated Metabolic Profiling and Gene Expression Analysis Reveals Therapeutic Modalities in Breast Cancer

Project description:Here, we report two distinctive groups defined by metabolites; a TNBC-HIGH group that shows high levels of pyrimidine pathway metabolites and biosynthetic enzymes, and an ER-HIGH group that shows high levels of fatty acid and arginine biosynthesis intermediates. We identify different metabolic enrichment profiles between cell lines grown in vitro vs. in vivo; cell lines grown in vivo recapitulate patient tumors metabolic profiles. Further, we identify a subset of genes that strongly correlates with the TNBC-HIGH metabolic profile using integrated metabolic and gene expression profiling, which strongly predicts patient prognosis when tested on larger human datasets. As a proof-of-principle, when we target TNBC-HIGH metabolic dysregulation with a pyrimidine biosynthesis inhibitor (Brequinar), and/or a glutaminase inhibitor (CB-839), we observe therapeutic efficacy and decreased tumor growth in representative TNBC cell lines, murine p53-null mammary tumors, and in vivo patient-derived xenografts (PDXs) upon multi-agent drug treatment. This study highlights potential new therapeutic opportunities in breast cancers guided by a genomic biomarker, which could prove impactful for breast cancers that rapidly proliferate.

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