Emergence of Enzalutamide resistance in prostate cancer is associated with BCL-2 and IKKB dependencies

xloma.fota13 shared this article with you from Inoreader Emergence of Enzalutamide resistance in prostate cancer is associated with BCL-2 and IKKB dependencies Via Clinical Cancer Research Online First Articles 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. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.