Author, as appears in the article.: 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.

Department: Enginyeria Electrònica, Elèctrica i Automàtica

URV's Author/s: Junza Martínez, Alexandra / Yanes Torrado, Óscar

Keywords: Stem-cells Risk Resistance Proliferation Parp inhibitors Oxphos Mutations Metformin Dna-damage response Diabetic-patients Chemotherapy Cancer-cell sensitivity Cancer metabolism Bcra parp inhibitors cancer metabolism oxphos bcra

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.

Thematic Areas: Molecular medicine Medicine, research & experimental Medicina veterinaria Medicina ii Medicina i Farmacia Ciências biológicas iii Ciências biológicas ii Ciências biológicas i

licence for use: https://creativecommons.org/licenses/by/3.0/es/

ISSN: 1757-4676

Author's mail: alexandra.junza@urv.cat oscar.yanes@urv.cat

Author identifier: 0000-0001-7205-0419 0000-0003-3695-7157

Record's date: 2023-02-26

Papper version: info:eu-repo/semantics/publishedVersion

Link to the original source: https://www.embopress.org/doi/full/10.15252/emmm.201911217

Licence document URL: http://repositori.urv.cat/ca/proteccio-de-dades/

Papper original source: Embo Molecular Medicine. 12 (e11217): e11217-

APA: 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., (2020). Tumors defective in homologous recombination rely on oxidative metabolism: relevance to treatments with PARP inhibitors. Embo Molecular Medicine, 12(e11217), e11217-. DOI: 10.15252/emmm.201911217

Article's DOI: 10.15252/emmm.201911217

Entity: Universitat Rovira i Virgili

Journal publication year: 2020

Publication Type: Journal Publications