Tumors defective in homologous recombination rely on oxidative metabolism: relevance to treatments with PARP inhibitors.

ABSTRACT: Mitochondrial metabolism and the generation of reactive oxygen species (ROS) contribute to the acquisition of DNA mutations and genomic instability in cancer. How genomic instability influences the metabolic capacity of cancer cells is nevertheless poorly understood. Here, we show that homologous recombination-defective (HRD) cancers rely on oxidative metabolism to supply NAD⁺ and ATP for poly(ADP-ribose) polymerase (PARP)-dependent DNA repair mechanisms. Studies in breast and ovarian cancer HRD models depict a metabolic shift that includes enhanced expression of the oxidative phosphorylation (OXPHOS) pathway and its key components and a decline in the glycolytic Warburg phenotype. Hence, HRD cells are more sensitive to metformin and NAD⁺ concentration changes. On the

SUBMITTER: Lahiguera A 

PROVIDER: S-EPMC7278557 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature