ABSTRACT
Prostate cancer (PCA) is the second leading cause of cancer-related deaths in men in the United States. It is natural for a hormone-driven malignancy such as prostate cancer that androgen deprivation therapy (ADT) would be the preferred treatment for clinical disease management. However, after initial treatment response a vast majority of patients develop metastatic castrate-resistant prostate cancer (CRPC), which is fatal. While great headway has been made to understand the possible mechanisms that drive castrate-resistant disease, a bonafide cure remains elusive. Reactivation of androgen receptor (AR) signaling partly contributes to the emergence of CRPC. Here we briefly examine some of the known mechanisms of AR reactivation including intratumoral synthesis of androgens, modulation of AR coregulators, and AR variants with constitutive activity as well as activation of receptor tyrosine kinases. We primarily focus on the emerging dual function of the receptor tyrosine kinase (recepteur d'origine nantais; RON) as a traditional tyrosine kinase and transcription factor. We further discuss activation of RON as an alternate mechanism in the development of CRPC and available therapeutic approaches for clinical management of CRPC by combined inhibition of RON and AR.