Selective Alanine Transporter Utilization Is a Therapeutic Vulnerability in ARID1A-Mutant Ovarian Cancer

Area of Science:

• Oncology
• Molecular Biology
• Cancer Metabolism

Background:

• SWI/SNF chromatin remodeling complex subunits are altered in ~20% of human cancers.
• ARID1A mutations are frequent in ovarian clear cell carcinoma (OCCC), a cancer with limited treatment options.

Purpose of the Study:

• To investigate the functional consequences of ARID1A mutations in cancer.
• To identify potential therapeutic vulnerabilities associated with ARID1A loss.

Main Methods:

• Analysis of ARID1A's regulation of alanine transporters (SLC38A2 and SLC7A8).
• Assessment of alanine utilization in ARID1A-mutant cells.
• Evaluation of SLC38A2 inhibition in OCCC models.
• Testing combination therapy with immunotherapy (CAR-T cells and anti-PD-L1).

Main Results:

• ARID1A mutations lead to increased intracellular alanine levels by repressing importer SLC38A2 and promoting exporter SLC7A8.
• ARID1A-mutant OCCC cells exhibit heightened dependence on alanine for protein synthesis and the TCA cycle.
• Inhibition of SLC38A2 selectively targets ARID1A-mutant OCCC.
• SLC38A2 inhibition enhances anti-tumor immunity, showing synergy with immunotherapy.

Conclusions:

• ARID1A mutations confer a metabolic vulnerability to alanine transport.
• Targeting alanine transport represents a potential therapeutic strategy for ARID1A-mutant cancers.
• Combination therapy of alanine transport inhibition with immunotherapy warrants further investigation.