Androgen Receptor Upregulation Mediates Radioresistance after Ionizing Radiation

Abstract

Clinical trials have established the benefit of androgen deprivation therapy (ADT) combined with radiotherapy (RT) in prostate cancer. ADT sensitizes prostate cancer to RT-induced death at least in part through inhibition of DNA repair machinery, but for unknown reasons adjuvant ADT provides further survival benefits. Here we show that androgen receptor (AR) expression and activity are durably upregulated following RT in multiple human prostate cancer models in vitro and in vivo. Moreover, the degree of AR upregulation correlates with survival in vitro and time to tumor progression in animal models. We also provide evidence of AR pathway upregulation, measured by a rise in serum levels of AR-regulated hK2 protein, in nearly 20 percent of patients after RT. Furthermore, these men were three fold more likely to experience subsequent biochemical failure. Collectively, these data demonstrate that RT can upregulate AR signaling post-therapy to an extent that negatively impacts disease progression and/or survival.

PET imaging of prostate-specific membrane antigen in prostate cancer: current state of the art and future challenges

“…40–43 Animal studies have shown that radiation is most effective for tumor reduction in combination with ADT. 44–46 This would agree with the increasing clinical evidence showing that biochemical response to ADT, as measured by PSA immediately before radiation, rather than duration of ADT is the critical factor for determining the benefit of combined treatment of radiation and ADT. 47–51 Recent studies have demonstrated that for men with clinically localized, nonmetastatic PCa receiving ADT and dose-escalated radiation, attaining a pre-RT PSA of <0.5 or ≤ 0.3 ng ml −1 after ADT, portends improved clinical outcomes, suggesting that the degree of suppression of AR signaling determines outcome in men treated with radiation.…”

Prostate Cancer Cells Express More Androgen Receptor (AR) Following Androgen Deprivation, Improving Recognition by AR-Specific T Cells

“…Radiotherapy enhances T cell-mediated tumor cell killing (33), and can enhance immune and antitumor responses when combined with immunotherapy both in pre-clinical models (34,35) as well as in patients with solid malignancies (36,37). Radiotherapy also increases AR expression in prostate cancer cell lines, likely as a DNA damage repair response, leading to increased AR signaling in patients treated with radiotherapy (38). This suggests that an AR-directed vaccine could synergize with radiation therapy.…”

Opportunities and challenges in combination gene cancer therapy

“…For example, castration and enzalutamide increase metastasis in both mouse and cell culture models of human prostate cancer, via the induction of the chemoattractant protein CCL2, which promotes migration of tumor cells and infiltration tumor-associated macrophages [30–34]. The observation of TIM in model systems is supported by some initial patient studies [32,35,36], indicating that combination therapies that include either anti-CCL2 monoclonal antibodies [37–40] or anti-CCR2 inhibitor [41] represent an additional opportunity to increase the efficacy of leuprorelin or enzalutamide in CRPC. Radiation therapy of prostate cancers increases expression of the AR, and reduces patient survival, suggesting that another single agent treatment for prostate cancer produces TIM and might effect might be reversed by additional combination therapies, such as the use of enzalutamide immediately following radiotherapy [36], and might also account for improved survival for patients receiving extended ADT following radiotherapy.…”