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

Author

Listed:
  • 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
    Paris City University, Inserm U1016, Faculty of Pharmaceutical and Biological Sciences)

  • Andrea Morandi

    (Viale Morgagni, 50 - 50134)

  • Elisabetta Marangoni

    (PSL University)

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.

Suggested Citation

  • 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 & Soph, 2023. "Oxidative phosphorylation is a metabolic vulnerability of endocrine therapy and palbociclib resistant metastatic breast cancers," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-40022-5
    DOI: 10.1038/s41467-023-40022-5
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    References listed on IDEAS

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    1. Elodie Montaudon & Joanna Nikitorowicz-Buniak & Laura Sourd & Ludivine Morisset & Rania El Botty & Léa Huguet & Ahmed Dahmani & Pierre Painsec & Fariba Nemati & Sophie Vacher & Walid Chemlali & Julien, 2020. "PLK1 inhibition exhibits strong anti-tumoral activity in CCND1-driven breast cancer metastases with acquired palbociclib resistance," Nature Communications, Nature, vol. 11(1), pages 1-16, December.
    2. Inmaculada Martínez-Reyes & Navdeep S. Chandel, 2020. "Mitochondrial TCA cycle metabolites control physiology and disease," Nature Communications, Nature, vol. 11(1), pages 1-11, December.
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    4. Samuel W. Brady & Jasmine A. McQuerry & Yi Qiao & Stephen R. Piccolo & Gajendra Shrestha & David F. Jenkins & Ryan M. Layer & Brent S. Pedersen & Ryan H. Miller & Amanda Esch & Sara R. Selitsky & Joel, 2017. "Combating subclonal evolution of resistant cancer phenotypes," Nature Communications, Nature, vol. 8(1), pages 1-15, December.
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