1. Tumors defective in homologous recombination rely on oxidative metabolism: relevance to treatments with PARP inhibitors
- Author
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Universitat Rovira i Virgili, Lahiguera Á., Hyroššová P., Figueras A., Garzón D., Moreno R., Soto-Cerrato V., McNeish I., Serra V., Lazaro C., Barretina P., Brunet J., Menéndez J., Matias-Guiu X., Vidal A., Villanueva A., Taylor-Harding B., Tanaka H., Orsulic S., Junza A., Yanes O., Muñoz-Pinedo C., Palomero L., Pujana M.À., Perales J.C., Viñals F., Universitat Rovira i Virgili, and Lahiguera Á., Hyroššová P., Figueras A., Garzón D., Moreno R., Soto-Cerrato V., McNeish I., Serra V., Lazaro C., Barretina P., Brunet J., Menéndez J., Matias-Guiu X., Vidal A., Villanueva A., Taylor-Harding B., Tanaka H., Orsulic S., Junza A., Yanes O., Muñoz-Pinedo C., Palomero L., Pujana M.À., Perales J.C., Viñals F.
- Abstract
© 2020 The Authors. Published under the terms of the CC BY 4.0 license 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 other hand, shifting from an OXPHOS to a highly glycolytic metabolism interferes with the sensitivity to PARP inhibitors (PARPi) in these HRD cells. This feature is associated with a weak response to PARP inhibition in patient-derived xenografts, emerging as a new mechanism to determine PARPi sensitivity. This study shows a mechanistic link between two major cancer hallmarks, which in turn suggests novel possibilities for specifically treating HRD cancers with OXPHOS inhibitors.
- Published
- 2020