Metabolic Approaches for ARID1A-Mutated Ovarian Cancer
Abstract
ARID1A encodes a subunit of the SWI/SNF chromatin-remodeling complex and functions as a tumor suppressor. Notably, inactivating mutations in ARID1A occur frequently in ovarian clear cell carcinomas (OCCC; greater than 50 percent) and ovarian endometrioid carcinomas (OEC; greater than 30 percent). There is an unmet need for effective treatment modalities for ARID1A-mutated ovarian cancers. Emerging evidence supports the idea that the SWI/SNF complexes play a critical role in the tumor metabolism. Our preliminary data show that ARID1A inactivation decreases glucose uptake and creates a dependence on the glutamine metabolism. Indeed, ARID1A inactivation sensitizes ovarian cancer to glutaminase (GLS) inhibition using a clinically applicable GLS inhibitor such as CB-839. In addition, there is evidence to support that the SWI/SNF complex inactivation renders tumors susceptible to checkpoint inhibition. Our preliminary data show that ARID1A mutation sensitizes ovarian cancer to anti-PD-L1 treatment. This is consistent with a recent publication showing that ARID1A mutation increases the PD-L1 expression in cancer cells. Notably, the competition for glutamine in the tumor microenvironment can suppress T cell proliferation. Consistently, the inhibition of GLS activity in tumor cells potentiate T cell proliferation without suppressing T cell function. Together, these findings raised the possibility that the inhibition of GLS activity in ARID1A-mutated ovarian cancer will not only suppresses the growth of ARID1Amutant cancer cells but also potentiate T cell proliferation and thus enhance checkpoint blockade therapy. Our central hypothesis is that ARID1A-mutated ovarian cancer can be therapeutically eradicated by the combination of a clinically applicable glutaminase inhibitor such as CB-839 andanti-PD-L1 immune checkpoint blockade.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2022
- Accession Number
- AD1197240
Entities
People
- Rugang Zhang
Organizations
- Wistar Institute