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

Area of Science:

• Cancer Biology
• Metabolic Reprogramming
• Chromatin Remodeling

Background:

• SMARCA4 and SMARCA2 are key ATPases in SWI/SNF chromatin remodeling complexes, often inactivated in cancers.
• While typically exhibiting synthetic lethality, concurrent SMARCA4/2 loss occurs in aggressive cancers with poor prognoses.

Purpose of the Study:

• To investigate the metabolic consequences of combined SMARCA4/2 loss in cancer.
• To identify therapeutic vulnerabilities associated with SMARCA4/2 deficiency.

Main Methods:

• Analysis of gene expression changes in SMARCA4/2-deficient cells.
• Assessment of glucose uptake, glycolysis, and oxidative phosphorylation (OXPHOS).
• Evaluation of sensitivity to metabolic inhibitors and amino acid supplementation in vitro and in vivo.

Main Results:

• SMARCA4/2 loss downregulates GLUT1, reducing glucose uptake and glycolysis, thereby increasing dependence on OXPHOS.
• Cells adapt by upregulating amino acid transporter SLC38A2 to import glutamine for OXPHOS.
• SMARCA4/2-deficient cells and tumors are sensitive to OXPHOS or glutamine metabolism inhibitors.
• Alanine supplementation, utilizing SLC38A2, selectively kills SMARCA4/2-deficient cells and synergizes with therapies.

Conclusions:

• SMARCA4/2 loss induces a metabolic shift towards OXPHOS, creating druggable vulnerabilities.
• Targeting OXPHOS or glutamine metabolism, particularly with alanine supplementation, offers a therapeutic strategy for aggressive SMARCA4/2-deficient cancers.