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Alanine supplementation exploits glutamine dependency induced by SMARCA4/2-loss

Author

Listed:
  • Xianbing Zhu

    (McGill University
    McGill University)

  • Zheng Fu

    (McGill University
    McGill University)

  • Shary Y. Chen

    (University of British Columbia
    British Columbia Cancer Research Institute)

  • Dionzie Ong

    (University of British Columbia)

  • Giulio Aceto

    (McGill University
    McGill University)

  • Rebecca Ho

    (University of British Columbia
    British Columbia Cancer Research Institute)

  • Jutta Steinberger

    (McGill University
    McGill University)

  • Anie Monast

    (McGill University
    McGill University)

  • Virginie Pilon

    (McGill University
    McGill University)

  • Eunice Li

    (University of British Columbia)

  • Monica Ta

    (University of British Columbia)

  • Kyle Ching

    (University of British Columbia)

  • Bianca N. Adams

    (McGill University
    McGill University)

  • Gian L. Negri

    (British Columbia Cancer Research Institute)

  • Luc Choiniere

    (McGill University)

  • Lili Fu

    (McGill University Health Centre)

  • Kitty Pavlakis

    (IASO women’s hospital)

  • Patrick Pirrotte

    (Translational Genomics Research Institute
    City of Hope Comprehensive Cancer Center)

  • Daina Z. Avizonis

    (McGill University)

  • Jeffrey Trent

    (Division of Integrated Cancer Genomics)

  • Bernard E. Weissman

    (University of North Carolina
    University of North Carolina)

  • Ramon I. Klein Geltink

    (University of British Columbia)

  • Gregg B. Morin

    (British Columbia Cancer Research Institute
    University of British Columbia)

  • Morag Park

    (McGill University
    McGill University)

  • David G. Huntsman

    (University of British Columbia
    British Columbia Cancer Research Institute
    University of British Columbia)

  • William D. Foulkes

    (Medicine and Oncology McGill University
    McGill University Health Centre
    McGill University)

  • Yemin Wang

    (University of British Columbia
    British Columbia Cancer Research Institute)

  • Sidong Huang

    (McGill University
    McGill University)

Abstract

SMARCA4 (BRG1) and SMARCA2 (BRM) are the two paralogous ATPases of the SWI/SNF chromatin remodeling complexes frequently inactivated in cancers. Cells deficient in either ATPase have been shown to depend on the remaining counterpart for survival. Contrary to this paralog synthetic lethality, concomitant loss of SMARCA4/2 occurs in a subset of cancers associated with very poor outcomes. Here, we uncover that SMARCA4/2-loss represses expression of the glucose transporter GLUT1, causing reduced glucose uptake and glycolysis accompanied with increased dependency on oxidative phosphorylation (OXPHOS); adapting to this, these SMARCA4/2-deficient cells rely on elevated SLC38A2, an amino acid transporter, to increase glutamine import for fueling OXPHOS. Consequently, SMARCA4/2-deficient cells and tumors are highly sensitive to inhibitors targeting OXPHOS or glutamine metabolism. Furthermore, supplementation of alanine, also imported by SLC38A2, restricts glutamine uptake through competition and selectively induces death in SMARCA4/2-deficient cancer cells. At a clinically relevant dose, alanine supplementation synergizes with OXPHOS inhibition or conventional chemotherapy eliciting marked antitumor activity in patient-derived xenografts. Our findings reveal multiple druggable vulnerabilities of SMARCA4/2-loss exploiting a GLUT1/SLC38A2-mediated metabolic shift. Particularly, unlike dietary deprivation approaches, alanine supplementation can be readily applied to current regimens for better treatment of these aggressive cancers.

Suggested Citation

  • Xianbing Zhu & Zheng Fu & Shary Y. Chen & Dionzie Ong & Giulio Aceto & Rebecca Ho & Jutta Steinberger & Anie Monast & Virginie Pilon & Eunice Li & Monica Ta & Kyle Ching & Bianca N. Adams & Gian L. Ne, 2023. "Alanine supplementation exploits glutamine dependency induced by SMARCA4/2-loss," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-38594-3
    DOI: 10.1038/s41467-023-38594-3
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