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

Abstract

Subunits of the SWI/SNF chromatin remodeling complex are altered in ~20% of human cancers. Exemplifying the alterations is the ARID1A mutation that occurs in ~50% ovarian clear cell carcinoma (OCCC), a disease with limited therapeutic options. Here, we showed that ARID1A mutations create a dependence on alanine by regulating alanine transporters to increase intracellular alanine levels. ARID1A directly repressed alanine importer SLC38A2 and simultaneously promoted alanine exporter SLC7A8. ARID1A inactivation increased alanine utilization predominantly in protein synthesis and passively through the tricarboxylic acid cycle. Indeed, ARID1A-mutant OCCCs were hyper-sensitive to inhibition of SLC38A2. In addition, SLC38A2 inhibition enhanced chimeric antigen receptor-T cell assault in vitro and synergized with immune checkpoint blockade using an anti-PD-L1 antibody in a genetically engineered mouse model of OCCC driven by conditional Arid1a inactivation in a CD8+ T-cell dependent manner. These findings suggest that targeting alanine transport alone or in combination with immunotherapy may represent an effective therapeutic strategy for ARID1A-mutant cancers.