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.
Cancer research. 2015 Oct 02 [Epub ahead of print]
Daniel E Spratt, Michael J Evans, Brian J Davis, Michael G Doran, Man Xia Lee, Neel Shah, John Wongvipat, Kathyrn E Carnazza, George G Klee, William Polkinghorn, Donald J Tindall, Jason S Lewis, Charles L Sawyers
Radiation Oncology, Memorial Sloan Kettering Cancer Center. , Human Oncology Pathogenesis Program, Memorial Sloan Kettering Cancer Center. , Radiation Oncology, Mayo Clinic. , Radiology, Memorial Sloan Kettering Cancer Center. , Human Oncology Pathogenesis Program, Memorial Sloan Kettering Cancer Center. , Human Oncology Pathogenesis Program, Memorial Sloan-Kettering Cancer Center. , Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center. , Radiology, Memorial Sloan Kettering Cancer Center. , Urology and Biochemistry/Molecular Biology, Mayo Clinic. , Radiation Oncology, Memorial Sloan Kettering Cancer Center. , Urology and Biochemistry/Molecular Biology, Mayo Clinic. , Radiochemistry Service, Department of Radiology, Memorial Sloan-Kettering Cancer Center. , Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center