Therapeutic Targeting of Mevalonate Pathway in 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 mutation suppresses the mevalonate pathway through downregulating rate-limiting enzymes such as 3-hydroxy-3-methylglutaryl-CoA synthase 1 (HMGCS1) and HMG-CoA reductase (HMGCR). The mevalonate pathway has previously been implicated in cancers due to its essential role in cell survival and proliferation. Indeed, ARID1A inactivation sensitizes ovarian cancer to the inhibition of residual mevalonate pathway activity using FDA approved, clinically applicable inhibitors such as Simvastatin and Atorvastatin. Pyroptosis is a lytic nonapoptotic cell death that triggers an inflammatory response. Our preliminary data suggest that statins induce pyroptosis in an ARID1A status dependent manner. In addition, our preliminary data show that ARID1A mutation sensitizes ovarian cancer to immune checkpoint blockades such as anti-PD-L1 treatment. Notably, pyroptosis induction in cancer cells promotes infiltration of immune cells such as CD8+ effective T cells that is required for the response to immune checkpoint blockades. Together, these findings raised the possibility that the inhibition of the mevalonate pathway by statins in ARID1A-mutated ovarian cancer will not only suppress the growth of ARID1A mutant cancer cells but also promote the infiltration of immune cells such as CD8+ effective T cells and thus enhance immune checkpoint blockade therapy.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2023
- Accession Number
- AD1219340
Entities
People
- Rugang Zhang
Organizations
- University of Pennsylvania