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

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IntroductionPersonalised 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.MethodsIsogenic CRISPR-Cas-mediated ATM-deficient and wild-type (WT) cells were treated with X-rays or Radium-223 dichloride (223Ra). 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.Results223Ra significantly increased radiosensitivity in comparison to X-rays which was amplified by ATM loss. 223Ra exposure in ATM-deficient cells induced significantly greater levels of DNA damage as measured by persistent 53BP1 foci at 24 h, distinct G2 accumulation and elevated levels of apoptosis in PC-3 and DU145 ATM-deficient cells in comparison to either X-rays or WT counterparts (p < 0.05). Furthermore, 223Ra triggered cGAS positive micronuclei and upregulation of STING driven inflammatory genes, particularly in ATM-deficient cells (p < 0.05).ConclusionsThese findings demonstrate that ATM-deficiency enhances radiobiological response and amplifies immune activation to 223Ra, supporting further pre-clinical evaluation of ATM loss as a determinant of response and therapeutic target to optimise 223Ra based strategies for mCRPC.

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