Stimulating Soluble Guanylyl Cyclase with the Clinical Agonist Riociguat Restrains the Development and Progression of Castration-Resistant Prostate Cancer

Castration-resistant prostate cancer (CRPC) is incurable and with noninvasive monitoring of cGMP levels as a marker for on-fatal, making prostate cancer the second leading cancer-related target efficacy. cause of death for American men. CRPC results from therapeutic resistance to standard-of-care androgen deprivation (AD) treat- Significance: Soluble guanylyl cyclase signaling inhibits casments, through incompletely understood molecular mechanisms, tration-resistant prostate cancer emergence and can be stimulated and lacks durable therapeutic options. In this study, we identified with FDA-approved riociguat to resensitize resistant tumors to enhanced soluble guanylyl cyclase (sGC) signaling as a mecha- androgen deprivation, providing a strategy to prevent and treat nism that restrains CRPC initiation and growth. Patients with castration resistance. aggressive, fatal CRPC exhibited significantly lower serum levels of the sGC catalytic product cyclic GMP (cGMP) compared with the castration-sensitive stage. In emergent castration-resistant cells isolated from castration-sensitive prostate cancer populations, the obligate sGC heterodimer was repressed via methylation of its β subunit. Genetically abrogating sGC complex formation in castration-sensitive prostate cancer cells promoted evasion of AD-induced senescence and concomitant castration-resistant tumor growth. In established castration-resistant cells, the sGC complex was present but in a reversibly oxidized and inactive state. Subjecting CRPC cells to AD regenerated the functional complex, and cotreatment with riociguat, an FDA-approved sGC agonist, evoked redox stress-induced apoptosis. Riociguat decreased castration-resistant tumor growth and increased apoptotic markers, with elevated cGMP levels correlating significantly with lower tumor burden. Riociguat treatment reorganized the tumor vasculature and eliminated hypoxic tumor niches, decreasing CD44⁺ tumor progenitor cells and increasing the radiosensitivity of castration-resistant tumors. Thus, this study showed that enhancing sGC activity can inhibit CRPC emergence and progression through tumor cell–intrinsic and extrinsic effects. Riociguat can be repurposed to overcome CRPC, with noninvasive monitoring of cGMP levels as a marker for on-target efficacy.