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Supplementary Fig. S7 from Emergence of Enzalutamide Resistance in Prostate Cancer is Associated with BCL-2 and IKKB Dependencies

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posted on 2023-03-31, 23:15 authored by Yi Liang, Sujeeve Jeganathan, Stefano Marastoni, Adam Sharp, Ines Figueiredo, Richard Marcellus, Amanda Mawson, Zvi Shalev, Aleksandra Pesic, Joan Sweet, Haiyang Guo, David Uehling, Bora Gurel, Antje Neeb, Housheng Hansen He, Bruce Montgomery, Marianne Koritzinsky, Samantha Oakes, Johann S. de Bono, Martin Gleave, Amina Zoubeidi, Bradly G. Wouters, Anthony M. Joshua

Emergence of ENZ resistance can be prevented by BCL-2 or IKKB inhibitor in vivo and is associated with IKKB upregulation

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Functional Assessment and Characterization of MDV3100-Resistant Cell Lines

Congressionally Directed Medical Research Programs

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Prostate Cancer Canada-Movember Team

Rising Star in Prostate Cancer Research

Medical Research Council

Academy of Medical Sciences

Prostate Cancer UK

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ARTICLE ABSTRACT

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. 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. 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. 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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