Investigating the Mechanisms of Resistance to Dual PI3K/MTOR Inhibitor in PIK3CA Mutant Basal Like Bladder Cancer

Abstract

Muscle invasive bladder cancer (MIBC) carries a poor prognosis where the overall 5 year survival ranges from 48% to 66%. To date, targeted therapies, except for immune checkpoint inhibitors have not been shown to be effective in the management of this disease, where conventional chemotherapy (i.e. cisplatin) continues to be the standard of care. Therefore, the challenge lies in identifying key molecular events that can predict response to targeted therapies and thereby provide patients with maximal clinical benefit. Using two MIBC patient derived xenograft models (PDX) that carry alterations in PI3K signaling, one of the most dysregulated signaling pathways in bladder cancer, we studied determinants of response to PI3K targeted inhibition and mechanisms of resistance. We found that PIK3CA mutation status as well as tumor subtype (luminal-like or basal-like) play cooperative role in driving treatment response, where PIK3CA E542K mutation in basal-like tumors is associated with resistance to PI3K inhibition. Resistance is driven by feedback activation of alternative feedback signaling such as RAS-MAPK pathway. Based on the mechanistic changes induced upon resistance, we tested different drug combinations that can overcome resistance to PI3K targeted inhibition. Interestingly, we observed bromodomain inhibition by JQ1 to be the most effective strategy to re-sensitize resistant cells to PI3K targeted therapy. Overall, this project provides a predictive paradigm of response to PI3K targeted inhibition in PIK3CA mutant MIBC and sets the stage for future rational clinical trial design.