Co-targeting the PI3K-Akt pathway improves response to MEK inhibition in low-grade serous ovarian cancer cell lines

Abstract

Low grade serous ovarian cancer (LGSOC) accounts for [~]5% of all ovarian cancers, with >1,000 new cases diagnosed each year in the United States. Currently, there is no established standard-of-care treatment for this subtype, and chemotherapy response rates are only [~]4%. One defining characteristic of LGSOC is a high prevalence of mutations within the MAPK pathway, which has motivated studies using MEK inhibitors to treat this disease. A recent phase II/III clinical trial using trametinib to treat patients with recurrent LGSOC improved the response rate to 26%; however, all patients eventually progressed due to the emergence of therapeutic resistance. Ongoing clinical trials are investigating combined inhibition of MEK and FAK with avutometinib plus defactinib for LGSOC patients, with preliminary results demonstrating response rates near 50%. While these results are highly encouraging, a significant subset of patients still fails to respond to existing targeted treatments. Additionally, development of therapeutic resistance in initial responders remains a major obstacle. Here, we sought to characterize molecular responses of LGSOC to MEK inhibition, both acutely and during the development of spontaneous drug resistance, with a goal of identifying adaptive mechanisms LGSOC cells utilize to withstand MAPK inhibition. Our research identified significant upregulation of the PI3K-Akt pathway in response to MEK inhibition. While targeted inhibition of AKT had minimal impact on its own, combination with MEK inhibitors produced strong synergistic suppression of proliferation in LGSOC cells. This combination strategy could potentially be used to prevent or reverse the emergence of MEK inhibitor resistance in LGSOC patients.