Targeting AR-Beclin 1 complex-modulated growth factor signaling increases the antiandrogen Enzalutamide sensitivity to better suppress the castration-resistant prostate cancer growth.

While the recently developed antiandrogen Enzalutamide (Enz) can extend survival for 4.8 months in castration-resistant prostate cancer (CRPC) patients, eventually most of these CRPC patients may develop resistance to the Enz without a clear mechanism. Here we found the expression of Beclin 1 was decreased in both Enz-resistant (EnzR) cell lines (EnzR1-C4-2 and EnzR2-C4-2B) as compared to their parental Enz-sensitive (EnzS) (EnzS1-C4-2 and EnzS2-C4-2B) cells, and targeting the Beclin 1 could lead to increase the Enz-sensitivity in these two CRPC cell lines. Mechanism dissection revealed that Enz might function via altering the interaction between Beclin 1 and the androgen receptor (AR) to decrease the activity of Beclin 1/Vps15/Vps34 complex thus increasing the ERK-mediated growth factor signaling to alter the Enz sensitivity. Interrupting the AR-Beclin 1/ERK signaling with ectopic BECN1 or ERK inhibitor led to alter the Enz sensitivity in both EnzR1-C4-2 and EnzR2-C4-2B cells compared to EnzS1-C4-2 and EnzS2-C4-2B cells, respectively. Together, these results suggest that targeting this newly identified AR-Beclin 1 complex-mediated ERK growth factor signaling with small molecule ERK inhibitor may help potentially develop new therapies to better suppress the EnzR CRPC.