A Review of the Pathophysiological Mechanisms Underlying Castration-resistant Prostate Cancer

Fionnuala Crowley,1 Michelle Sterpi,1 Conor Buckley,1 Lauren Margetich,1 Shivani Handa,1 Zach Dovey2 1Department of Internal Medicine, Icahn School of Medicine, Mount Sinai Morningside and West, New York, NY, USA; 2Department of Urology, Icahn School of Medicine, Mount Sinai Hospital, New York, NY, USACorrespondence: Shivani HandaDepartment of Internal Medicine, Mount Sinai Morningside and West, 1000 Tenth Avenue, New York, NY, 10019, USATel +1-917-520-3693Email Shivani.Handa@mountsinai.orgAbstract: Androgen deprivation therapy or ADT is one of the cornerstones of management of locally advanced or metastatic prostate cancer, alongside radiation therapy. However, despite early response, most advanced prostate cancers progress into an androgen unresponsive or castrate resistant state, which hitherto remains an incurable entity and the second leading cause of cancer-related mortality in men in the US. Recent advances have uncovered multiple complex and intermingled mechanisms underlying this transformation. While most of these mechanisms revolve around androgen receptor (AR) signaling, novel pathways which act independently of the androgen axis are also being discovered. The aim of this article is to review the pathophysiological mechanisms that help bypass the apoptotic effects of ADT to create castrate resistance. The article discusses castrate resistance mechanisms under two categories: 1. Direct AR dependent pathways such as amplification or gain of function mutations in AR, development of functional splice variants, posttranslational regulation, and pro-oncogenic modulation in the expression of coactivators vs corepressors of AR. 2. Ancillary pathways involving RAS/MAP kinase, TGF-beta/SMAD pathway, FGF signaling, JAK/STAT pathway, Wnt-Beta catenin and hedgehog signaling as well as the role of cell adhesion molecules and G-protein coupled receptors. miRNAs are also briefly discussed. Understanding the mechanisms involved in the development and progression of castration-resistant prostate cancer is paramount to the development of targeted agents to overcome these mechanisms. A number of targeted agents are currently in development. As we strive for more personalized treatment across oncology care, treatment regimens will need to be tailored based on the type of CRPC and the underlying mechanism of castration resistance.Keywords: castration resistance, prostate cancer, androgen-deprivation therapy, androgen insensitivity, androgen recepto