Investigation of resistance mechanisms in response to PIK3CA inhibition in breast cancer

Abstract

Breast cancer is the most frequently diagnosed cancer type, accounting for 25% of total cancer cases. PI3K pathway is the most deregulated pathway in breast cancer. Therefore, many inhibitors have been developed for druggable pathway constituents. PIK3CA, which codes for p110α catalytic domain of PI3K, is often found to be mutated in breast cancer patients, resulting in overactivation of PI3K signaling. Recent FDA approval of Alpelisib (BYL719), a p110α-specific small molecule inhibitor, has proven to be effective in hormone receptor positive advanced or metastatic breast cancer patients with activating PIK3CA mutations. Despite its superior efficacy compared to pan-PI3K inhibitors, therapy resistance is still the major problem. AKT has been viewed as the main kinase that relays oncogenic PI3K signal further downstream. Recent studies have revealed readily known kinases that function independent of AKT to be involved in PIK3CA resistance in a PI3K-dependent manner. In this study, we aimed to identify novel molecular targets within the PI3K pathway, but signal in an AKT-independent manner that can confer resistance to PIK3CA inhibition. Our bioinformatical analyses identified STK10 as a potential candidate. STK10 knockdown was able to sensitize breast cancer cells to BYL-719 and induce cell growth in untransformed cell. Moreover, we developed BYL-719 resistant Luminal A subtype breast cancer cell lines to further study additional mechanisms of resistance. Our resistant cell line models had sustained AKT, S6 and 4EBP1 phosphorylation compared to wild-type counterparts under BYL-719 inhibition. Future transcriptomic and proteomic analyses to be performed on these cell lines will provide new insights on BYL-719 resistance mechanisms and help identify novel molecular targets for new therapeutic approaches in combatting BYL-719 resistance in patients.