Oxidative phosphorylation is a metabolic vulnerability of endocrine therapy and palbociclib resistant metastatic breast cancers

Rania El-Botty, Ludivine Morriset, Elodie Montaudon, Zakia Tariq, Anne Schnitzler, Marina Bacci, Nicla Lorito, Laura Sourd, Léa Huguet, Ahmed Dahmani, Pierre Painsec, Heloise Derrien, Sophie Vacher, Julien Masliah-Planchon, Virginie Raynal, Sylvain Baulande, Thibaut Larcher, Anne Vincent-Salomon, Guillaume Dutertre, Paul Cottu, Géraldine Gentric, Fatima Mechta-Grigoriou, Scott Hutton, Keltouma Driouch, Ivan Bièche, Andrea Morandi and Elisabetta Marangoni ()
Additional contact information
Rania El-Botty: PSL University
Ludivine Morriset: PSL University
Elodie Montaudon: PSL University
Zakia Tariq: PSL University
Anne Schnitzler: PSL University
Marina Bacci: Viale Morgagni, 50 - 50134
Nicla Lorito: Viale Morgagni, 50 - 50134
Laura Sourd: PSL University
Léa Huguet: PSL University
Ahmed Dahmani: PSL University
Pierre Painsec: PSL University
Heloise Derrien: PSL University
Sophie Vacher: PSL University
Julien Masliah-Planchon: PSL University
Virginie Raynal: PSL University
Sylvain Baulande: PSL University
Thibaut Larcher: Oniris
Anne Vincent-Salomon: PSL University
Guillaume Dutertre: PSL University
Paul Cottu: PSL University
Géraldine Gentric: PSL University
Fatima Mechta-Grigoriou: PSL University
Scott Hutton: Metabolon Inc.
Keltouma Driouch: PSL University
Ivan Bièche: PSL University
Andrea Morandi: Viale Morgagni, 50 - 50134
Elisabetta Marangoni: PSL University

Nature Communications, 2023, vol. 14, issue 1, 1-16

Abstract: Abstract Resistance to endocrine treatments and CDK4/6 inhibitors is considered a near-inevitability in most patients with estrogen receptor positive breast cancers (ER + BC). By genomic and metabolomics analyses of patients’ tumours, metastasis-derived patient-derived xenografts (PDX) and isogenic cell lines we demonstrate that a fraction of metastatic ER + BC is highly reliant on oxidative phosphorylation (OXPHOS). Treatment by the OXPHOS inhibitor IACS-010759 strongly inhibits tumour growth in multiple endocrine and palbociclib resistant PDX. Mutations in the PIK3CA/AKT1 genes are significantly associated with response to IACS-010759. At the metabolic level, in vivo response to IACS-010759 is associated with decreased levels of metabolites of the glutathione, glycogen and pentose phosphate pathways in treated tumours. In vitro, endocrine and palbociclib resistant cells show increased OXPHOS dependency and increased ROS levels upon IACS-010759 treatment. Finally, in ER + BC patients, high expression of OXPHOS associated genes predict poor prognosis. In conclusion, these results identify OXPHOS as a promising target for treatment resistant ER + BC patients.

Date: 2023
References: View references in EconPapers View complete reference list from CitEc
Citations: View citations in EconPapers (1)

Downloads: (external link)
https://www.nature.com/articles/s41467-023-40022-5 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-40022-5

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-023-40022-5

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().