Castration-resistant prostate cancer (CRPC) is incurable and fatal, making prostate cancer the second-leading cancer-related cause of death for American men. CRPC results from therapeutic resistance to standard-of-care androgen deprivation (AD) treatments, through incompletely understood molecular mechanisms, and lacks durable therapeutic options. Here, we identified enhanced soluble guanylyl cyclase (sGC) signaling as a mechanism that restrains CRPC initiation and growth. Patients with aggressive, fatal CRPC exhibited significantly lower serum levels of the sGC catalytic product cyclic GMP (cGMP) compared to their castration-sensitive stage. In emergent castration-resistant cells isolated from castration-sensitive prostate cancer (CSPC) populations, the obligate sGC heterodimer was repressed via methylation of its beta subunit. Genetically abrogating sGC complex formation in CSPC 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 co-treatment 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 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.
Cancer research. 2024 Oct 10 [Epub ahead of print]
Ling Zhang, Clara I Troccoli, Beatriz Mateo-Victoriano, Laura Misiara Lincheta, Erin Jackson, Ping Shu, Trisha Plastini, Wensi Tao, Deukwoo Kwon, X Steven Chen, Janaki Sharma, Merce Jorda, Surinder Kumar, David B Lombard, James L Gulley, Marijo Bilusic, Albert C Lockhart, Annie Beuve, Priyamvada Rai
University of Miami, Miami, FL, United States., New Jersey Medical School Rutgers, Newark, NJ, United States., Cleveland Clinic Florida, Weston, FL, United States., University of Miami Health System, Miami, Florida, United States., UTHealth Science Center at Houston, Houston, Texas, United States., Braman Family Breast Cancer Institute, MIAMI, FL, United States., University of Miami Health System, Miami, FL, United States., Miller School of Medicine, and Sylvester Comprehensive Cancer Center, University of Miami, and Miami VA Healthcare System, Miami, FL, United States., National Cancer Institute, Bethesda, MD, United States., Medical University of South Carolina, Charleston, South Carolina, United States., Rutgers, The State University of New Jersey, newark, NJ, United States.