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

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. Negri, Luc Choiniere, Lili Fu, Kitty Pavlakis, Patrick Pirrotte, Daina Z. Avizonis, Jeffrey Trent, Bernard E. Weissman, Ramon I. Klein Geltink, Gregg B. Morin, Morag Park, David G. Huntsman, William D. Foulkes, Yemin Wang () and Sidong Huang ()
Additional contact information
Xianbing Zhu: McGill University
Zheng Fu: McGill University
Shary Y. Chen: University of British Columbia
Dionzie Ong: University of British Columbia
Giulio Aceto: McGill University
Rebecca Ho: University of British Columbia
Jutta Steinberger: McGill University
Anie Monast: McGill University
Virginie Pilon: 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
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
Daina Z. Avizonis: McGill University
Jeffrey Trent: Division of Integrated Cancer Genomics
Bernard E. Weissman: University of North Carolina
Ramon I. Klein Geltink: University of British Columbia
Gregg B. Morin: British Columbia Cancer Research Institute
Morag Park: McGill University
David G. Huntsman: University of British Columbia
William D. Foulkes: Medicine and Oncology McGill University
Yemin Wang: University of British Columbia
Sidong Huang: McGill University

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

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-38594-3

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