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


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 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 in vitro and in vivo, and used knockdown and overexpression 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 ENZ/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.

Type Journal
ISBN 1557-3265 (Electronic) 1078-0432 (Linking)
Authors Liang, Y.; Jeganathan, S.; Marastoni, S.; Sharp, A.; Figueiredo, I.; Marcellus, R.; Mawson, A.; Shalev, Z.; Pesic, A.; Sweet, J.; Guo, H.; Uehling, D.; Gurel, B.; Neeb, A.; He, H. H.; Montgomery, B.; Koritzinsky, M.; Oakes, S.; de Bono, J. S.; Gleave, M.; Zoubeidi, A.; Wouters, B. G.; Joshua, A. M.
Responsible Garvan Author Prof Anthony Joshua
Published Date 2021-04-30
Published Volume 27
Published Issue 8
Published Pages 2340-2351
Status Published in-print
DOI 10.1158/1078-0432.CCR-20-3260
URL link to publisher's version