Author ORCID Identifier

https://orcid.org/0000-0001-6486-3794

Date Available

8-10-2024

Year of Publication

2022

Degree Name

Doctor of Philosophy (PhD)

Document Type

Doctoral Dissertation

College

Medicine

Department/School/Program

Toxicology and Cancer Biology

First Advisor

Dr. Xiaoqi Liu

Abstract

Prostate cancer (PCa) ranks as the most diagnosed type of cancer and the second leading cause of death in men. Androgen receptor (AR) signaling plays a pivotal function in promoting the survival and progression of PCa. Therefore, medication for PCa mainly focuses on the inhibition of AR pathway, which is termed androgen deprivation therapy (ADT). However, the disease eventually progresses and develops to a lethal stage called castration-resistant prostate cancer (CRPC) that is characterized by resistance to canonical ADT. To deal with this situation, several second-generation AR inhibitors (SG-ARIs) have been created that have better efficacy against AR, including Enzalutamide (ENZ), Apalutamide (APA) and Darolutamide (DARO). Unfortunately, response to SG-ARIs usually doesn’t last for long time, and generation of resistance is inevitable. Thus, how to enhance the therapeutic efficacy and overwhelm resistance to SG-ARIs remains to be a major dilemma.

Through our sequencing analysis, we identified elevated level of erythropoietin-producing human hepatocellular receptor B4 (EphB4) and glutathione S-transferase Mu 2 (GSTM2) in ENZ-resistant PCa. While EPHB4 is a receptor tyrosine kinase associated with many biological events, GSTM2 is a phase II metabolizing enzyme and serves as an antioxidant. Co-targeting EphB4 or GSTM2 is effective in overcoming resistance to SG-ARIs and re-sensitizing PCa to treatment. Mechanistically, EphB4 pathway induces resistance to ENZ through the overexpression of AR, and GSTM2 contributes to resistance to SG-ARIs by fighting against treatment-induced oxidative stress and activation of p38 MAPK pathway. Taking together, our findings provide novel insight into the molecular mechanism responsible for the generation of drug resistance and render methods to improve the therapeutic efficacy of SG-ARIs in clinical scenarios.

Digital Object Identifier (DOI)

https://doi.org/10.13023/etd.2022.302

Funding Information

This study was supported by the National Institutes of Health R01 grants CA157429, CA192894, CA196835, CA196634, CA264652 and CA256893 from 2017-2022.

This study was supported by the Biospecimen Procurement & Translational Pathology, Biostatistics and Bioinformatics, Redox Metabolism, and Flow Cytometry and Immune Monitoring Shared Resources of the University of Kentucky Markey Cancer Center (P30CA177558) from 2018-2022.

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