Selective killing of castration‐resistant prostate cancer cells by formycin A via the ATF4–CHOP axis

Prostate cancer is initially androgen‐dependent but often relapses to an androgen‐independent state called castration‐resistant prostate cancer (CRPC). Currently approved therapies have limited efficacy against CRPC, highlighting the need for novel therapeutic strategies. To address this need, we conducted a drug screen in our previously established aggressive CRPC cell model. We found that formycin A induced cell death in CRPC model cells but not in parental prostate cancer cells. In addition, formycin A upregulated death receptor 5 through the induction of endoplasmic reticulum stress, activating the “extrinsic” apoptosis pathway in CRPC model cells. Moreover, formycin A showed in vivo antitumor efficacy against CRPC xenografts in castrated nude mice. Thus, our findings highlight the potential of formycin A as a CRPC therapeutic. Our drug screen identified formycin A as effective in inducing cell death specifically in CRPC cells through the upregulation of death receptor 5 and activation of the extrinsic apoptosis pathway. Additionally, formycin A demonstrated antitumor efficacy in vivo, suggesting its potential as a CRPC therapeutic.