Blocking PI3K p110β Attenuates Development of PTEN-Deficient Castration-Resistant Prostate Cancer

A common outcome of androgen deprivation in prostate cancer therapy is disease relapse and progression to castration-resistant prostate cancer (CRPC) via multiple mechanisms. To gain insight into the recent clinical findings that highlighted genomic alterations leading to hyperactivation of PI3K, we examined the roles of the commonly expressed p110 catalytic isoforms of PI3K in a murine model of Pten-null invasive CRPC. While blocking p110 alpha had negligible effects in the development of Pten-null invasive CRPC, either genetic or pharmacologic perturbation of p110 beta dramatically slowed CRPC initiation and progression. Once fully established, CRPC tumors became partially resistant to p110 beta inhibition, indicating the acquisition of new dependencies. Driven by our genomic analyses highlighting potential roles for the p110 beta/RAC/PAK1 and beta-catenin pathways in CRPC, we found that combining p110 beta with RAC/PAK1 or tankyrase inhibitors significantly reduced the growth of murine and human CRPC organoids in vitro and in vivo. Because p110 beta activity is dispensable for most physiologic processes, our studies support novel therapeutic strategies both for preventing disease progression into CRPC and for treating CRPC.

Automated summary

Research findings suggest that blocking p110 beta can slow down the progression of castration-resistant prostate cancer and reduce tumor growth. Combining p110 beta with other inhibitors shows potential for treating CRPC.