Open AccessTumors defective in homologous recombination rely on oxidative metabolism: relevance to treatments with PARP inhibitors
Author(s) -
Lahiguera Álvaro,
Hyroššová Petra,
Figueras Agnès,
Garzón Diana,
Moreno Roger,
SotoCerrato Vanessa,
McNeish Iain,
Serra Violeta,
Lazaro Conxi,
Barretina Pilar,
Brunet Joan,
Menéndez Javier,
MatiasGuiu Xavier,
Vidal August,
Villanueva Alberto,
TaylorHarding Barbie,
Tanaka Hisashi,
Orsulic Sandra,
Junza Alexandra,
Yanes Oscar,
MuñozPinedo Cristina,
Palomero Luís,
Pujana Miquel Àngel,
Perales José Carlos,
Viñals Francesc
Publication year - 2020
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.15252/emmm.201911217
Subject(s) - homologous recombination , poly adp ribose polymerase , oxidative phosphorylation , metabolism , genetics , homologous chromosome , parp inhibitor , oxidative metabolism , chemistry , microbiology and biotechnology , biology , cancer research , computational biology , biochemistry , dna , gene , polymerase
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 ( PARP i) 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 PARP i 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.