A low-androgen environment sustains redox-active sGC states required to restrain castration-resistant prostate cancer growth via elevated cGMP levels

Castration-resistant prostate cancer (CRPC) remains incurable and fatal, creating a dire need for new safe and effective treatment strategies. We recently reported that the soluble guanylyl cyclase (sGC) stimulator, riociguat, cooperates with standard-of-care androgen deprivation (AD) to inhibit castration-resistant tumor burden by oxygenating hypoxic tumor niches and inducing tumor apoptosis. We further found that AD restores the sensitivity of CRPC cells to riociguat, which requires a redox-active functional sGC complex to stimulate cyclic GMP (cGMP) production. As redox reprogramming is a feature of the low-androgen PC milieu, to better establish the parameters of riociguat efficacy, we wished to determine whether redox-inactive forms of sGC persist in the castrate setting. To do so, we treated CRPC LNAI tumor-bearing animals with cinaciguat, an sGC activator which preferentially acts on the oxidized sGC complex. We found that, compared to riociguat, cinaciguat did not significantly increase intratumoral or systemic cGMP levels in the castrate setting. Nor did cinaciguat treatment significantly decrease tumor burden or oxygenate the hypoxic CRPC tumors. Given the preferential activity of cinaciguat on the redox-inactive sGC complex, our results indicate that the low-androgen castrate setting maintains the sGC complex in its functionally reduced state, affirming the critical benefit of AD for riociguat efficacy in the lethal castration-resistant disease stage.