Pathogenic mitochondrial DNA variants are associated with response to anti-VEGF therapy in ovarian cancer PDX models

Background: Mitochondrial DNA (mtDNA) pathogenic variants have been reported in several solid tumors including ovarian cancer (OC), the most lethal gynecologic malignancy, and raised interest as they potentially induce mitochondrial dysfunction and rewiring of cellular metabolism. Despite advances in recent years, functional characterization of mtDNA variants in cancer and their possible modulation of drug response remain largely uncharted. Methods: Here, we characterized mtDNA variants in OC patient derived xenografts (PDX) and investigated their impact on cancer cells at multiple levels. Results: Genetic analysis revealed that mtDNA variants predicted as pathogenic, mainly involving complex I and IV genes, were present in all but one PDX (n = 20) at different levels of heteroplasmy, including 7 PDXs with homoplasmic variants. Functional analyses demonstrated that pathogenic mtDNA variants impacted on respiratory complexes activity and subunits abundance as well as on mitochondrial morphology. Moreover, PDX cells bearing homoplasmic mtDNA variants behaved as glucose-addicted and could barely survive glucose starvation in vitro. RNA-seq analysis indicated that mtDNA mutated (heteroplasmy > 50%) PDXs were endowed with upregulated glycolysis and other pathways connected with cancer metabolism. These findings led us to investigate whether pathogenic mtDNA variants correlated with response to anti-VEGF therapy, since the latter was shown to reduce glucose availability in tumors. Strikingly, PDXs bearing homoplasmic pathogenic mtDNA variants associated with improved survival upon anti-VEGF treatment in mice, compared with mtDNA wild type or low heteroplasmy PDXs. Conclusions: These results hint at mtDNA variants as potential biomarkers of response to antiangiogenic drugs.