Synergistic Efficacy of Gedatolisib and Darolutamide in Prostate Cancer to Overcome Resistance to Androgen-Targeted Therapy.

The oncogenic activation of the PI3K/AKT/mTOR (PAM) pathway, which is often associated with loss of PTEN, is an important adaptive mechanism to androgen-targeted therapy in castration-resistant prostate cancer (CRPC). The concomitant targeting of the PAM pathway and the androgen receptor (AR) pathway is a promising therapeutic strategy for CRPC. Many PAM pathway inhibitors only target one component of the PAM pathway, which can limit efficacy due to the activation of the uninhibited components. We previously showed that the multi-target pan-PI3K-mTORC1/2 inhibitor, gedatolisib, exerts greater growth-inhibitory effects than single-target PAM pathway inhibitors in prostate cancer (PC) cells, regardless of PTEN or AR status. In the present study, we investigated the molecular and cellular effects of gedatolisib in combination with darolutamide in both PTEN+ and PTEN-deficient PC cell lines, including AR+ PC cell lines adapted to long-term treatment with darolutamide. We found that the gedatolisib + darolutamide combination exerted greater anti-proliferative and cytotoxic effects than the single agents in most AR+ PC cell models, regardless of their PTEN status. The gedatolisib + darolutamide combination inhibited AR and PAM pathway activities, blocked cell cycle progression, induced apoptotic cell death, and reduced glucose and lipid metabolism. The drug combination was effective in both darolutamide-naïve and darolutamide-adapted cell lines, suggesting potential benefit in prostate tumors that progressed after androgen-targeted therapy. These results provide a strong rationale for clinical studies evaluating gedatolisib in combination with AR inhibitors in CRPC.