Prostate cancer is the most commonly diagnosed cancer in men and nearly 30,000 patients will die this year due to complications arising from the disease. Prostate cancer patients are frequently treated with androgen deprivation therapies, but the duration of response is variable, and patients frequently progress to an incurable stage of the disease referred to as castration-resistant prostate cancer (CRPC). Second-generation AR antagonists such as enzalutamide and apalutamide are effective therapies that block androgen receptor (AR) transactivation and signaling in over 50% of CRPC patients. However, an estimated 30% of responders will develop resistance to these therapies within two years. There is another class of AR antagonists which are referred to as pan AR antagonists, that have shown to inhibit the activity of wild-type AR as well as several mutated versions of AR. Currently, there are several pan AR antagonists in preclinical development and approved for the treatment of CRPC in patients harboring pathogenic point mutations in AR. We chose four genetically distinct AR-positive prostate cancer preclinical models to generate enzalutamide, JNJ-pan-AR, or apalutamide resistant cell lines. We then performed transcriptomic and proteomic profiling on the AR antagonist sensitive and resistant cell lines to uncover molecular alterations that may be critical to the maintenance and/ or predictive biomarkers of the resistant phenotype. Global profiling uncovered significant variability in molecular alterations across the AR antagonist resistant cell lines as well as the prostate cancer preclinical models. However, we uncovered upregulation of AKR1C3 protein expression across all three AR antagonist resistant cell lines using the LNCaP and LNCaP/AR preclinical models. Further characterization of the functional significance of AKR1C3 upregulation demonstrated that AKR1C3 protein expression contributes to JNJ-pan-AR resistance. Similar findings have reported the correlation between AKR1C3 expression and changes in drug efficacy across several chemotherapeutic agents approved to CRPC treatment. Collectively the findings from this study support the rationale of AKR1C3 as a target for AR antagonist resistant prostate cancer disease progression.
|Advisor:||Janetopoulos, Christopher J.|
|Commitee:||Heindl, Jason E., McDevitt, Theresa M., Rupnow, Brent A., Mercier, Isabelle|
|School:||University of the Sciences in Philadelphia|
|Department:||Cell & Molecular Biology|
|School Location:||United States -- Pennsylvania|
|Source:||DAI-B 82/5(E), Dissertation Abstracts International|
|Subjects:||Cellular biology, Oncology, Molecular biology, Epidemiology, Health care management, Public health|
|Keywords:||AR antagonists, CRPC, Prostate cancer|
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