Molecular Pathways Driving Enzalutamide Resistance in Prostate Cancer: Roles of Notch Signaling and DNA Methyltransferases

Prostate cancer is the second leading cause of cancer-related death among men in the United States. The androgen receptor (AR) antagonist enzalutamide is an FDA-approved therapy for patients with late-stage prostate cancer and is currently under clinical investigation for the treatment of early-stage disease. Although patients often show an initial favorable response to enzalutamide, tumors inevitably develop drug resistance. In this review, we summarize current knowledge of prostate cancer, with a particular focus on disease diagnosis, AR signaling, and available treatment options. We provide an in-depth discussion of enzalutamide, a major therapeutic agent for castration-resistant prostate cancer, emphasizing both AR-dependent and AR-independent mechanisms of resistance. We also review the Notch signaling pathway, including Notch family members, mechanisms of pathway activation, its role in prostate cancer progression, and crosstalk between Notch and AR signaling. In addition, we discuss DNA methylation, covering the structure and function of DNA methyltransferases, the role of DNA methylation in development and adult tissues, its involvement in prostate cancer, its regulation of key cellular pathways and processes, and its contribution to drug resistance. Finally, we highlight our recent findings on the roles of Notch signaling and DNA methyltransferases in enzalutamide resistance in prostate cancer.