Computational analysis of androgen receptor dependent radiosensitivity in prostate cancer

Abstract

In this study, we quantitatively analyze the mechanism by which androgen deprivation therapy (ADT) is enhancing radiosensitivity in prostate cancer (PCa) patients. It has been shown in laboratory experiments, as well as in patient data in the literature, that the androgen receptor (AR) reduces the effectiveness of ionizing radiation treatment by enhancing the non-homologous end joining (NHEJ) repair of radiation damage. The suppression of AR by ADT suppresses the activity of NHEJ that leads to radiosensitivity in PCa patients. In this paper, we have studied this positive interaction between AR and NHEJ using mathematical models of the NHEJ that we have developed using both the experimental and clinical data for PCa. Our results show that the biological observation of suppression of AR by ADT leading to down-regulation of the first NHEJ protein Ku and NHEJ is a plausible biological mechanism that explains both the experimental and clinical observations in the literature. The presented analysis is the first step in quantitatively analyzing possible treatment scenarios to find the optimal treatment strategies for PCa using the combination treatment with ADT, NHEJ inhibitors, and IR.