Blocking GRP/GRP-R signaling decreases expression of androgen receptor splice variants and inhibits tumor growth in castration-resistant prostate cancer

Clinical management of castration-resistant prostate cancer (CRPC) resulting from androgen deprivation therapy (ADT) remains challenging. Many studies indicate that receptor splice variants (ARVs) play a critical role in the development CRPC, including resistance to new generation inhibitors (AR) action. ARVs are constitutively active and lack ligand-binding domain (LBD), thereby allowing (PC) maintain AR activity despite therapies target (full-length AR; AR-FL). Previously, we have reported long-term ADT increases neuroendocrine (NE) hormone – Gastrin Releasing Peptide (GRP) its (GRP-R) expression PC cells. Further, demonstrated activation GRP/GRP-R signaling by activating NF-?B signaling, promoting progression CRPC. Most importantly, as cell surface protein, GRP-R is easily targeted drugs block signaling. In this study, tested if blocking targeting using antagonist sufficient control CRPC progression. Our show RC-3095, selective antagonist, efficiently inhibits (AR-V7) therapy-induced NEPC (tNEPC) addition, can sensitize cells anti-androgen treatment (such MDV3100). preclinical animal combination (targeting ARVs) with AR-FL) inhibit tNEPC tumor growth.