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 (NT5E or CD73) as a major determinant of metabolic phenotypes in
cancer cells. NT5E expression and associated metabolome
variations were also correlated with sensitivity to several chemotherapeutics
including platinum-based treatment. NT5E 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 NT5E 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 NT5E 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 NT5E inhibition and that NT5E expression may be a useful prognostic and predictive clinical biomarker.