Inhibitory function of CDK12i combined with WEE1i on castration-resistant prostate cancer cells in vitro and in vivo

Abstract Objective The inhibitors of CDK12 and WEE1 (SR-4835 and AZD-1775) have rarely been evaluated in studies on castration-resistant prostate cancer (CRPC) treatment. The research objective of this article is to study the inhibitory effect of SR-4835 and AZD-1775 on CRPC cells and to explore the therapeutic effect of combining the two drugs in the treatment of CRPC cells in vitro and in vivo . Methods We performed Western blot, quantitative real-time PCR, Cell Counting Kit-8, colony formation, EdU, and immunofluorescence assays; cell cycle analysis, wound scratch and Transwell assays and nude mice xenograft tumor analysis to identify the mechanism and measure the therapeutic effect of SR-4835, AZD-1775 and the combination in CRPC cells. Results Compared with normal prostate cells, the expressions of CDK12 and WEE1 in prostate cancer cells, especially CRPC cells, were significantly increased at protein and mRNA levels. SR-4835 can cause DNA damage in CRPC cells by inhibiting the expression of DNA damage repair genes. AZD-1775 inhibits the G2/M phase checkpoint function. Performing in vivo and in vitro experiments, we found that SR-4835 combined with AZD-1775 significantly enhanced the inhibitory effect on CRPC cell to a greater degree than monotherapy. Conclusions In summary, SR-4835 combined with AZD-1775 can eliminate CRPC cells by inducing DNA damage and inhibiting the normal repair machinery. Therefore, we consider this combination therapy to be a promising strategy for CRPC patients.