Androgen Receptor Signaling Fuels DNA Repair and Radioresistance in Prostate Cancer

“Successful treatment by genotoxic modalities including radiotherapy is commonly hampered by treatment resistance in advanced cancers. Two new studies now reveal that androgen receptor signaling transcriptionally upregulates a large subset of DNA repair genes, thereby enhancing the repair capacity and promoting radioresistance of prostate cancer. These results provide a mechanistic rationale for a combined treatment by ionizing radiation and androgen deprivation therapy.”

Understanding Why

“For patients with high-risk prostate cancer, treatment with both androgen deprivation therapy (ADT) and ionizing radiation (IR) improves progression-free and overall survival and has long been the standard of care. Two papers published in Cancer Discovery unveil the molecular mechanisms that underpin this clinical response.”

Androgen Receptor Signaling Regulates DNA Repair in Prostate Cancers

“We demonstrate that the androgen receptor (AR) regulates a transcriptional program of DNA repair genes that promotes prostate cancer radioresistance, providing a potential mechanism by which androgen deprivation therapy (ADT) synergizes with ionizing radiation (IR). Using a model of castration-resistant prostate cancer, we show that second-generation antiandrogen therapy results in downregulation of DNA repair genes. Next, we demonstrate that primary prostate cancers display a significant spectrum of AR transcriptional output which correlates with expression of a set of DNA repair genes. Employing RNA-seq and ChIP-seq, we define which of these DNA repair genes are both induced by androgen and represent direct AR targets. We establish that prostate cancer cells treated with IR plus androgen demonstrate enhanced DNA repair and decreased DNA damage and furthermore that antiandrogen treatment causes increased DNA damage and decreased clonogenic survival. Finally, we demonstrate that antiandrogen treatment results in decreased classical non-homologous end joining.”

Metformin Inhibits Growth and Enhances Radiation Response of Non-Small Cell Lung Cancer (NSCLC) Through ATM and AMPK

“We examined the potential of metformin (MET) to enhance non-small cell lung cancer (NSCLC) responses to ionising radiation (IR)…”