ArticleNature communications2023
Alanine supplementation exploits glutamine dependency induced by SMARCA4/2-loss.
Article in Nature communications, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed, 29 citations in OpenAlex.
- Glutamine metabolism in health and disease.Signal transduction and targeted therapy · 2026Review
- TGF-β coordinates alanine synthesis and import for myofibroblast differentiation in pulmonary fibrosis.JCI insight · 2026Article
- Bibliometric analysis and knowledge mapping of thoracic SMARCA4-deficient undifferentiated tumor.Discover oncology · 2026Article
- The SWI/SNF complex in tumor metabolism: Mechanisms and therapeutic implications.The Journal of biological chemistry · 2026Review
- SMARCA4/2 loss reduces BCL-xL expression and confers a druggable MCL1 dependency in cancer.NPJ precision oncology · 2026Article
- Selective Alanine Transporter Utilization Is a Therapeutic Vulnerability in ARID1A-Mutant Ovarian Cancer.Cancer research · 2025Article
- Targeting ALDH16A1 mediated thioredoxin lysosomal degradation to enhance ferroptosis susceptibility in SMARCA4-deficient NSCLC.Nature communications · 2025Article
- The role of SMARCA4 in lung cancer.Scientific reports · 2025Review
- Molecular subtyping of endometrial carcinoma cell lines uncovers subtype-specific targetable vulnerabilities.NPJ precision oncology · 2025Article
- Review
- Chromatin remodeling and cancer: the critical influence of the SWI/SNF complex.Epigenetics & chromatin · 2025Review
- Glutamate dehydrogenase 1-catalytic glutaminolysis feedback activates EGFR/PI3K/AKT pathway and reprograms glioblastoma metabolism.Neuro-oncology · 2025Article
- Organoid drug profiling identifies methotrexate as a therapy for SCCOHT, a rare pediatric cancer.Science advances · 2025Article
- Tumor-agnostic therapy: a potential therapeutic approach for SMARCA4-deficient malignancies.Therapeutic advances in medical oncology · 2025Review
- Targeting emerging amino acid dependencies and transporters in cancer therapy.Frontiers in pharmacology · 2025Review
- BRG1 improves reprogramming efficiency by enhancing glycolytic metabolism.Cellular and molecular life sciences : CMLS · 2024Article
- CD169+ Macrophages Mediate the Immune Response of Allergic Rhinitis Through the Keap1/Nrf2/HO-1 Axis.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2024Article
- Tumor energy metabolism: implications for therapeutic targets.Molecular biomedicine · 2024Review
- Therapeutic modulation of ROCK overcomes metabolic adaptation of cancer cells to OXPHOS inhibition and drives synergistic anti-tumor activity.bioRxiv : the preprint server for biology · 2024Article
- [Research Progress on SMARCA4 Mutation Non-small Cell Lung Cancer].Zhongguo fei ai za zhi = Chinese journal of lung cancer · 2024Review
Corrections and comments
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Authors and funding
28 authors at 8 institutions in 3 countries.
Funding
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.
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