Emergence of Enzalutamide Resistance in Prostate Cancer is Associated with BCL-2 and IKKB Dependencies.
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ICR Authors
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, HH
Montgomery, B
Koritzinsky, M
Oakes, S
de Bono, JS
Gleave, M
Zoubeidi, A
Wouters, BG
Joshua, AM
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, HH
Montgomery, B
Koritzinsky, M
Oakes, S
de Bono, JS
Gleave, M
Zoubeidi, A
Wouters, BG
Joshua, AM
Document Type
Journal Article
Date
2021-04-15
Date Accepted
2021-02-02
Date Available
2021-04-07T14:20:05Z
Abstract
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.
Citation
Clinical cancer research : an official journal of the American Association for Cancer Research, 2021
Source Title
Publisher
AMER ASSOC CANCER RESEARCH
ISSN
1078-0432
eISSN
1557-3265
Collections
Research Team
Prostate Cancer Targeted Therapy Group
Prostate Cancer Targeted Therapy Group
Prostate Cancer Targeted Therapy Group