Enhanced Response to Radiopharmaceutical Therapy in Preclinical Tumor Models with XRD-0394, a Dual Inhibitor of ATM Kinase and DNA-PKcs.

Enhanced DNA repair is a common mechanism of radiation resistance. XRD-0394, a novel small molecule dual inhibitor of ataxia telangiectasia mutated (ATM) kinase and deoxyribonucleic acid (DNA)-dependent protein kinase (DNA-PKcs), may sensitize tumor cells to killing by external beam radiation therapy (EBRT) or radiopharmaceutical therapy (RPT). DNA damage response inhibition and increased cytotoxicity were observed in Myc-CaP prostate cancer tumor cells after irradiation + XRD-0394 as indicated by the inhibition of radiation- induced phosphorylation of KAP1, p53, and H2A.X and decreased clonogenic potential. In mice bearing the FaDu head and neck squamous cell carcinoma (HNSCC) xenograft tumor model, the combination of irradiation or 177Lu-NM600 + XRD-0394 improved tumor response and overall survival compared to monotherapy controls. Increased expression of type I interferon response genes was observed after irradiation + XRD-0394 compared to irradiation alone, suggesting that XRD-0394 may also accentuate the immunogenic effects of radiation on tumor cells. Further investigation is warranted into treatment approaches that combine radiopharmaceutical therapies, DNA repair inhibitors, and immunotherapies.