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Title: Tumors defective in homologous recombination rely on oxidative metabolism: relevance to treatments with PARP inhibitors
Author: Lahiguera, Álvaro
Hyrossová, Petra
Figueras i Amat, Agnès
Garzón, Diana
Moreno, Roger
Soto Cerrato, Vanessa
McNeish, Iain
Serra, Violeta
Lázaro García, Conxi
Barretina, Pilar
Brunet, Joan
Menéndez, Javier A.
Matias-Guiu, Xavier
Vidal-Bel, August
Villanueva Garatachea, Alberto
Taylor-Harding, Barbie
Tanaka, Hisashi
Orsulic, Sandra
Junza Martínez, Alexandra
Yanes, Oscar
Muñoz Pinedo, Cristina
Palomero, Luis
Pujana Genestar, M. Ángel
Perales Losa, Carlos
Viñals Canals, Francesc
Keywords: Tumors
Inhibidors enzimàtics
Enzyme inhibitors
Issue Date: 13-May-2020
Publisher: EMBO Press
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 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.
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It is part of: EMBO Molecular Medicine, 2020, p. e11217
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ISSN: 1757-4676
Appears in Collections:Articles publicats en revistes (Infermeria Fonamental i Clínica)
Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))
Articles publicats en revistes (Patologia i Terapèutica Experimental)
Articles publicats en revistes (Ciències Fisiològiques)

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