Exploiting Dependence of Castration-Resistant Prostate Cancer on the Arginine Vasopressin Signaling Axis by Repurposing Vaptans

Men with advanced prostate cancer are treated by androgen deprivation therapy but the disease recurs as incurable castrationWe previously demonstrated that the G protein-coupled receptor expressed in CRPC and promotes castration-resistant growth in vitro and in vivo. AVPR1A is part of a family of GPCR's including prostate cancer patient sample data revealed that coexpression of AVPR1A and AVPR2 is highly correlated with disease progression. Stimulation of AVPR2 with a selective agonist desmopressin promoted CRPC cell proliferation through cAMP/protein kinase A signaling, consistent with AVPR2 coupling to the G protein subunit alpha s. In contrast, blocking AVPR2 with a selective FDAxenografts, antagonizing AVPR2, AVPR1A, or both significantly reduced CRPC tumor growth as well as decreased on-target markers of tumor burden. Combinatorial use of AVPR1A and AVPR2 antagonists promoted apoptosis synergistically in CRPC cells. Furthermore, we found that castration-resistant cells produced AVP, the endogenous ligand for arginine vasopressin receptors, and knockout of AVP in CRPC cells significantly reduced proliferation suggesting possible AVP autocrine signaling. These data indicate that the AVP/arginine vasopressin receptor signaling axis represents a promising and clinically actionable target for CRPC.