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

  • Nat Commun. 2023 Jul 14;14(1):4221. doi: 10.1038/s41467-023-40022-5.
Rania El-Botty  1 ,  Ludivine Morriset  1 ,  Elodie Montaudon  1 ,  Zakia Tariq  2 ,  Anne Schnitzler  2 ,  Marina Bacci  3 ,  Nicla Lorito  3 ,  Laura Sourd  1 ,  Léa Huguet  1 ,  Ahmed Dahmani  1 ,  Pierre Painsec  1 ,  Heloise Derrien  1 ,  Sophie Vacher  2 ,  Julien Masliah-Planchon  2 ,  Virginie Raynal  4 ,  Sylvain Baulande  4 ,  Thibaut Larcher  5 ,  Anne Vincent-Salomon  6 ,  Guillaume Dutertre  7 ,  Paul Cottu  8 ,  Géraldine Gentric  9 ,  Fatima Mechta-Grigoriou  9 ,  Scott Hutton  10 ,  Keltouma Driouch  2 ,  Ivan Bièche  2  11 ,  Andrea Morandi  3 ,  Elisabetta Marangoni  12
Affiliations
  • 1. Laboratory of Preclinical Investigation, Translational Research Department, Institut Curie, PSL University, 26 rue d'Ulm, 75005, Paris, France.
  • 2. Department of Genetics, Institut Curie, PSL University, 26 rue d'Ulm, 75005, Paris, France.
  • 3. Dept. of Experimental and Clinical Biomedical Sciences, Viale Morgagni, 50 - 50134, Florence, Italy.
  • 4. ICGex - NGS platform, Institut Curie, PSL University, 26 rue d'Ulm, 75005, Paris, France.
  • 5. INRA, APEX-PAnTher, Oniris, 44322, Rue de la Géraudière, Nantes, France.
  • 6. Department of Pathology, Institut Curie, PSL University, 26 rue d'Ulm, 75005, Paris, France.
  • 7. Department of Surgery, Institut Curie, PSL University, 26 rue d'Ulm, 75005, Paris, France.
  • 8. Department of Medical Oncology, Institut Curie, PSL University, 26 rue d'Ulm, 75005, Paris, France.
  • 9. "Stress and Cancer" Laboratory, Institut Curie - Inserm U830, PSL University, 26 rue d'Ulm, 75005, Paris, France.
  • 10. Metabolon Inc., 617 Davis Drive, Suite 100, Morrisville, NC, 27560, USA.
  • 11. Paris City University, Inserm U1016, Faculty of Pharmaceutical and Biological Sciences, 75005, Paris, France.
  • 12. Laboratory of Preclinical Investigation, Translational Research Department, Institut Curie, PSL University, 26 rue d'Ulm, 75005, Paris, France. [email protected].
PMID: 37452026 DOI: 10.1038/s41467-023-40022-5
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.

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