A Systems Oncology Approach Identifies NT5E as a Key Metabolic Regulator in Tumor Cells and Modulator of Platinum Sensitivity

Altered metabolism in tumor cells is required for rapid proliferation but also can influence other phenotypes that affect clinical outcomes such as metastasis and sensitivity to chemotherapy. Here, a genome-wide association study (GWAS)-guided integration of NCI-60 transcriptome and metabolome data identified ecto-5'-nucleotidase (NYSE or CD73) as a major determinant of metabolic phenotypes in cancer cells. NYSE expression and associated metabolome variations were also correlated with sensitivity to several chemotherapeutics including platinum-based treatment. NYSE mRNA levels were observed to be elevated in cells upon in vitro and in vivo acquisition of platinum resistance in ovarian cancer cells, and specific targeting of NYSE increased tumor cell sensitivity to platinum. We observed that tumor NT5E levels were prognostic for outcomes in ovarian cancer and were elevated after treatment with platinum, supporting the translational relevance of our findings. In this work, we integrated and analyzed a plethora of public data, demonstating the merit of such a systems oncology approach for the discovery of novel players in cancer biology and therapy. We experimentally validated the main findings of the NYSE gene being involved in both intrinsic and acquired resistance to platinum-based drugs. We propose that the efficacy of conventional chemotherapy could be improved by NYSE inhibition and that NYSE expression may be a useful prognostic and predictive clinical biomarker.