Emergence of Enzalutamide Resistance in Prostate Cancer is Associated with BCL-2 and IKKB Dependencies.

Abstract

Although enzalutamide (ENZ) has been widely used to treat <i>de novo</i> 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. We selected several ENZ-resistant cell lines that replicated clinical characteristics of the majority of patients with ENZ-resistant disease. A high-throughput pharmacologic screen was utilized to identify compounds with greater cytotoxic effect for ENZ-resistant cell lines, compared with parental ENZ-sensitive cells. We validated the potential hits <i>in vitro</i> and <i>in vivo</i>, and used knockdown and overexpression assays to study the dependencies in ENZ-resistant prostate cancer. ABT199 (BCL-2 inhibitor) and IMD0354 (IKKB inhibitor) were identified as potent and selective inhibitors of cell viability in ENZ-resistant cell lines <i>in vitro</i> and <i>in vivo</i> 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 ENZ/abiraterone resistance in patients, only the protein levels of IKKB were increased. Our findings identify BCL-2 and IKKB dependencies in clinically relevant ENZ-resistant prostate cancer cells <i>in vitro</i> and <i>in vivo</i>, but indicate that IKKB upregulation appears to have greater relevance to the progression of human castrate-resistant prostate cancer.