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

Abstract

Inhibidors de la PARP; Metabolisme del càncer; Metformina

Inhibidores de PARP, Metabolismo del cáncer; Metformina

PARP inhibitors; Cancer metabolism; Metformin

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.

This study has been funded by the Ministerio de Ciencia, Innovación y Universidades, which is part of the Agencia Estatal de Investigación (AEI), through the project SAF2017-85869-R (cofunded by the European Regional Development Fund (ERDF), a way to build Europe) to FV and BFU2015-66030-R to JCP; by the FIS PI15/00854 and FIS PI16/01898 (Instituto Carlos III, cofunded by FEDER funds/European Regional Development Fund (ERDF), a way to build Europe) to MAP and AVillanueva and with the support of the Secretariat for Universities and Research of the Department of Business and Knowledge of the Government of Catalonia (2017SGR449) to FV. We thank the CERCA Program/Generalitat de Catalunya for their institutional support. We particularly wish to acknowledge the collaboration of the patients and the IDIBGI Biobank (Biobanc IDIBGI, B.0000872), which is part of the Spanish National Biobank Network and the Xarxa de Bancs de Tumors de Catalunya (XBTC), financed by the Pla Director d'Oncologia de Catalunya, Spain. We thank Cristina Saura (Breast Cancer & Melanoma Group) and people from the Experimental Therapeutics Group at VHIO and Sara González (Unitat de Diagnòstic Molecular, ICO-Duran i Reynals). We thank H. Simon, R. Bartrons, and A. Manzano (Universitat de Barcelona) and A. Vaquero (IDIBELL) for reagents.