The double-edged sword of androgen signaling for selective radiosensitization of prostate cancer cells

The majority of prostate cancers (PCa) require androgen receptor (AR) signaling for growth and survival; as such, AR inhibition, through surgical or chemical castration to deplete androgen hormones or with pharmacological inhibitors of AR, has been a mainstay for treatment of PCa. Paradoxically, recent studies have demonstrated that supraphysiologic androgen exposure can also inhibit prostate cancer growth, with recent clinical trials demonstrating that administration of high-dose testosterone to men with castration-resistant PCa can be safe, lead to clinical responses, and even resensitize castration-resistant cells to androgen blockade. The inhibitory effect of supraphysiological androgens on PCa growth likely reflects topoisomerase II-dependent induction of DNA double-strand breaks (DSB) during relief of transcription-associated topological stress under high-dose androgen stimulation. Given that double-strand breaks can enhance sensitivity to ionizing radiation, we propose leveraging AR-driven DNA damage by delivering pulsatile AR stimulation in the setting of androgen deprivation, timed immediately prior to radiation fractions, to achieve selective radiosensitization. Furthermore, alternative AR ligands may radiosensitize PCa cells while limiting activation of AR-mediated expression of growth/survival transcriptional programs in high-risk PCa.