Impact of ataxia-telangiectasia mutated (ATM) loss on radiobiological and immune response to radium-223 in prostate cancer in vitro models.

INTRODUCTION: Personalised medicine approaches are redefining the therapeutic landscape for men with metastatic castration-resistant prostate cancer (mCRPC). While poly(ADP-ribose) polymerase (PARP) inhibitors have demonstrated clinical benefit in patients with BRCA1/2 mutant tumours, the therapeutic efficacy of these inhibitors in Ataxia-telangiectasia mutated (ATM)-mutated prostate cancer patients remains modest, highlighting the need for alternative treatment strategies. This study aimed to elucidate the impact of ATM loss on radiobiological and immune responses to different radiation modalities in prostate cancer models. METHODS: Ra). Cellular radiosensitivity was measured using clonogenic assays and 53BP1 immunofluorescence assessed DNA damage. Cell cycle distribution and apoptosis were analysed by flow cytometry. Innate immune activation was assessed using cGAS immunofluorescence and quantitative PCR of CCL5, CXCL10 and IFIT2. RESULTS: Ra triggered cGAS positive micronuclei and upregulation of STING driven inflammatory genes, particularly in ATM-deficient cells (p < 0.05). CONCLUSIONS: Ra based strategies for mCRPC.