Aryl Hydrocarbon Receptor Promotes Enzalutamide Resistance Through Diverse Mechanisms in Castration-Resistant Prostate Cancer

Chia-Hui Chen

Prostate cancer (PC) is the most common and second most lethal cancer for men in theU.S. and the world. Despite a high five-year survival rate, therapy-resistant prostate cancer is currently incurable and is responsible for more than 30,000 deaths annually in the U.S.. Enzalutamide (ENZ) is the first FDA-approved second-generation antiandrogen to treat ad vanced PC and has been in clinical use for a decade. However,clinical benefits of ENZ is greatly limited by the inevitable development of acquired resistance, rendering it not cura tive. To alleviate this global health burden, understanding molecular mechanisms of therapy resistance is key to developing effective and sophisticated ways of managing prostate can cer. The first chapter of this dissertaion summarizes the literature on prostate cancer, ENZ resistance, and the target gene of this dissertation, the aryl hydrocarbon recetpor (AHR). The second chapter describes the discovery of AHR as a candidate gene using by analyzing expression profiles from ENZ-resistant (ENZR) castration-resistant prostate cancer (CRPC) cell lines and clinical high-grade PC samples after ENZ treatment. The functional impor tance of AHR has been verified by shRNA-based disruption of AHR expression in both in vitro and in vivo in a nude mice xenograft model. The third chapter explores the molecular mechanisms underlying AHR-mediated ENZ resistance in two ENZR CRPC cell lines: C4-2BENZR and,CWR-R1ENZR by comparing transcriptional changes between control and AHR knockdown cell lines. Evidence shows that AHR functions through different mech anisms to promote growth in these two cell lines. In CWR-R1ENZR, AHR replenishes the androgen receptor (AR) signaling by driving the glucocorticoid receptor (GR) pathway and increasing expression of AR-GR co-target genes. In C4-2BENZR, AHR promotes neuroen docrine (NE) differentiation, a driver for AR-independence in PC. As a result, AHR is found to promote both AR-dependent and AR-independent mechanisms of ENZ resistance. The fourth chapter utilizes an unbiased CRISPR genetic screen to interrogate the role of AHR in C4-2BENZR cells. Guides targeting AHR has been found consistently decrease in the ENZ treatment group, suggesting its importance in maintaing ENZ resistance. This dissertation presents AHR as a growth regulator of ENZR CRPC. Importantly, AHR functions in a context-dependent manner to promote growth in ENZ resistant prostate cancer cell lines with different etiology and genetic background. Given the heterogeneity of prostate cancer, AHR offers a unique opportunity as a multifaceted therapeutic target, providing valuable insights into the molecular base of therapy resistance in prostate cancer.

Aryl Hydrocarbon Receptor Promotes Enzalutamide Resistance Through Diverse Mechanisms in Castration-Resistant Prostate Cancer

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