Purpose:Although enzalutamide (ENZ) has been widely used to treat de novo or castration-resistant metastatic prostate cancer, resistance develops, and disease progression is ultimately inevitable. There are currently no approved targeted drugs to specifically delay or overcome ENZ-resistance. Experimental Design:We selected several ENZ-resistant cell lines that replicated clinical characteristics of the majority of patients with ENZ-resistant disease. A high- throughput pharmacological screen was utilized to identify compounds with greater cytotoxic effect for ENZ-resistant cell lines, compared to parental ENZ-sensitive cells. We validated the potential hits in vitro and in vivo, and used knock-down and over- expression assays to study the dependencies in ENZ-resistant prostate cancer. Results:ABT199 (BCL-2 inhibitor) and IMD0354 (IKKB inhibitor), were identified as potent and selective inhibitors of cell viability in ENZ-resistant cell lines in vitro and in vivo which were further validated using loss-of-function assays of BCL-2 and IKKB. Notably, we observed that overexpression of BCL-2 and IKKB in ENZ-sensitive cell lines was sufficient for the emergence of ENZ resistance. In addition, we confirmed that BCL-2 or IKKB inhibitors suppressed the development of ENZ resistance in xenografts. However, validation of both BCL-2 and IKKB in matched castration-sensitive/resistant clinical samples showed that, concurrent with the development of enzalutamide/abiraterone resistance in patients, only the protein levels of IKKB were increased. Conclusions:Our findings identify BCL-2 and IKKB dependencies in clinically relevant ENZ-resistant prostate cancer cells in vitro and in vivo but indicate that IKKB upregulation appears to have greater relevance to the progression of human castrate resistant prostate cancer.
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