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

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 re...

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Autores: Lahiguera, Álvaro, Hyroššová, Petra, Figueras, Agnès, Garzón, Diana, Moreno, Roger, Soto‐Cerrato, Vanessa, McNeish, Iain, Serra, Violeta, Lázaro, Conxi, Barretina, Pilar, Brunet, Joan, Menéndez, Javier, Matias-Guiu, Xavier, Vidal, August, Villanueva, Alberto, Taylor‐Harding, Barbie, Tanaka, Hisashi, Orsulic, Sandra, Junza, Alexandra, Yanes, Óscar, Muñoz‐Pinedo, Cristina, Palomero, Luís, Pujana, Miguel Angel, Perales, José Carlos, Viñals, Francesc
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2020
País:España
Institución:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repositorio:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:10459.1/467696
Acceso en línea:https://doi.org/10.15252/emmm.201911217
https://hdl.handle.net/10459.1/467696
Access Level:acceso abierto
Palabra clave:BCRA
Cancer metabolism
Metformin
OXPHOS
PARP inhibitors
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spelling Tumors defective in homologous recombination rely on oxidative metabolism: relevance to treatments with PARP inhibitorsLahiguera, ÁlvaroHyroššová, PetraFigueras, AgnèsGarzón, DianaMoreno, RogerSoto‐Cerrato, VanessaMcNeish, IainSerra, VioletaLázaro, ConxiBarretina, PilarBrunet, JoanMenéndez, JavierMatias-Guiu, XavierVidal, AugustVillanueva, AlbertoTaylor‐Harding, BarbieTanaka, HisashiOrsulic, SandraJunza, AlexandraYanes, ÓscarMuñoz‐Pinedo, CristinaPalomero, LuísPujana, Miguel AngelPerales, José CarlosViñals, FrancescBCRACancer metabolismMetforminOXPHOSPARP inhibitorsMitochondrial 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.SpringerEMBO Press2020info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttps://doi.org/10.15252/emmm.201911217https://hdl.handle.net/10459.1/467696reponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)InglésReproducció del document publicat a: https://doi.org/10.15252/emmm.201911217EMBO Molecular Medicine, 2020, vol. 12, núm. 6, e11217cc-by (c)The Authors, 2020Attribution 4.0 Internationalinfo:eu-repo/semantics/openAccesshttp://creativecommons.org/licenses/by/4.0/oai:recercat.cat:10459.1/4676962026-05-29T05:05:01Z
dc.title.none.fl_str_mv Tumors defective in homologous recombination rely on oxidative metabolism: relevance to treatments with PARP inhibitors
title Tumors defective in homologous recombination rely on oxidative metabolism: relevance to treatments with PARP inhibitors
spellingShingle Tumors defective in homologous recombination rely on oxidative metabolism: relevance to treatments with PARP inhibitors
Lahiguera, Álvaro
BCRA
Cancer metabolism
Metformin
OXPHOS
PARP inhibitors
title_short Tumors defective in homologous recombination rely on oxidative metabolism: relevance to treatments with PARP inhibitors
title_full Tumors defective in homologous recombination rely on oxidative metabolism: relevance to treatments with PARP inhibitors
title_fullStr Tumors defective in homologous recombination rely on oxidative metabolism: relevance to treatments with PARP inhibitors
title_full_unstemmed Tumors defective in homologous recombination rely on oxidative metabolism: relevance to treatments with PARP inhibitors
title_sort Tumors defective in homologous recombination rely on oxidative metabolism: relevance to treatments with PARP inhibitors
dc.creator.none.fl_str_mv Lahiguera, Álvaro
Hyroššová, Petra
Figueras, Agnès
Garzón, Diana
Moreno, Roger
Soto‐Cerrato, Vanessa
McNeish, Iain
Serra, Violeta
Lázaro, Conxi
Barretina, Pilar
Brunet, Joan
Menéndez, Javier
Matias-Guiu, Xavier
Vidal, August
Villanueva, Alberto
Taylor‐Harding, Barbie
Tanaka, Hisashi
Orsulic, Sandra
Junza, Alexandra
Yanes, Óscar
Muñoz‐Pinedo, Cristina
Palomero, Luís
Pujana, Miguel Angel
Perales, José Carlos
Viñals, Francesc
author Lahiguera, Álvaro
author_facet Lahiguera, Álvaro
Hyroššová, Petra
Figueras, Agnès
Garzón, Diana
Moreno, Roger
Soto‐Cerrato, Vanessa
McNeish, Iain
Serra, Violeta
Lázaro, Conxi
Barretina, Pilar
Brunet, Joan
Menéndez, Javier
Matias-Guiu, Xavier
Vidal, August
Villanueva, Alberto
Taylor‐Harding, Barbie
Tanaka, Hisashi
Orsulic, Sandra
Junza, Alexandra
Yanes, Óscar
Muñoz‐Pinedo, Cristina
Palomero, Luís
Pujana, Miguel Angel
Perales, José Carlos
Viñals, Francesc
author_role author
author2 Hyroššová, Petra
Figueras, Agnès
Garzón, Diana
Moreno, Roger
Soto‐Cerrato, Vanessa
McNeish, Iain
Serra, Violeta
Lázaro, Conxi
Barretina, Pilar
Brunet, Joan
Menéndez, Javier
Matias-Guiu, Xavier
Vidal, August
Villanueva, Alberto
Taylor‐Harding, Barbie
Tanaka, Hisashi
Orsulic, Sandra
Junza, Alexandra
Yanes, Óscar
Muñoz‐Pinedo, Cristina
Palomero, Luís
Pujana, Miguel Angel
Perales, José Carlos
Viñals, Francesc
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv BCRA
Cancer metabolism
Metformin
OXPHOS
PARP inhibitors
topic BCRA
Cancer metabolism
Metformin
OXPHOS
PARP inhibitors
description 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.
publishDate 2020
dc.date.none.fl_str_mv 2020
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://doi.org/10.15252/emmm.201911217
https://hdl.handle.net/10459.1/467696
url https://doi.org/10.15252/emmm.201911217
https://hdl.handle.net/10459.1/467696
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Reproducció del document publicat a: https://doi.org/10.15252/emmm.201911217
EMBO Molecular Medicine, 2020, vol. 12, núm. 6, e11217
dc.rights.none.fl_str_mv cc-by (c)The Authors, 2020
Attribution 4.0 International
info:eu-repo/semantics/openAccess
http://creativecommons.org/licenses/by/4.0/
rights_invalid_str_mv cc-by (c)The Authors, 2020
Attribution 4.0 International
http://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv Springer
EMBO Press
publisher.none.fl_str_mv Springer
EMBO Press
dc.source.none.fl_str_mv reponame:Recercat. Dipósit de la Recerca de Catalunya
instname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
instname_str Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
reponame_str Recercat. Dipósit de la Recerca de Catalunya
collection Recercat. Dipósit de la Recerca de Catalunya
repository.name.fl_str_mv
repository.mail.fl_str_mv
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