Prostate cancer is the most commonly diagnosed and second-most lethal
cancer among men in the United States. The vast majority of
prostate cancer deaths are due to
castration-resistant
prostate cancer (CRPC) - the lethal form of the disease that has progressed despite
therapies that interfere with activation of
androgen receptor (AR) signaling. One emergent resistance mechanism to medical
castration is synthesis of intratumoral
androgens that activate the AR. This insight led to the development of the AR antagonist
enzalutamide. However, resistance to
enzalutamide invariably develops, and
disease progression is nearly universal. One mechanism of resistance to
enzalutamide is an F877L mutation in the AR
ligand-binding domain that can convert
enzalutamide to an agonist of AR activity. However, mechanisms that contribute to the agonist switch had not been fully clarified, and there were no
therapies to block AR F877L. Using cell line models of
castration-resistant
prostate cancer (CRPC), we determined that cellular
androgen content influences
enzalutamide agonism of mutant F877L AR. Further,
enzalutamide treatment of AR F877L-expressing cell lines recapitulated the effects of
androgen activation of F877L AR or wild-type AR. Because the BET bromodomain inhibitor JQ-1 was previously shown to block
androgen activation of wild-type AR, we tested JQ-1 in AR F877L-expressing CRPC models. We determined that JQ-1 suppressed
androgen or
enzalutamide activation of mutant F877L AR and suppressed growth of mutant F877L AR CRPC
tumors in vivo, demonstrating a new strategy to treat
tumors harboring this mutation.