ATM and ATR inhibition increases radiosensitivity and cGAS-STING activation in prostate cancer

Despite the availability of multiple effective therapies for localized prostate cancer, many patients still progress to incurable metastasized castration resistant prostate cancer (mCRPC). About 23 % of mCRPC patients carry alterations in DNA damage response (DDR) genes, including the protein kinases Ataxia telangiectasia mutated (ATM). DDR gene mutations have been shown to increase radiosensitivity and responses to immunotherapy. Here, we aimed to investigate the effect of inhibiting ATM and Ataxia telangiectasia and Rad3 related (ATR) on the radiosensitivity and subsequent activation of the cGAS-STING pathway in three prostate cancer cell lines. The data demonstrate that ATM and ATR inhibition leads to increased radiosensitivity in the PC3 and DU145 cell lines and that simultaneous inhibition of ATM and ATR results in enhanced cell death after irradiation. Furthermore, ATM blockade or combined ATM and ATR inhibition, but not ATR inhibition alone, significantly enhances radiation-induced cGAMP levels and a gene expression signature induced by the cytokine type I interferon. This work highlights the promising effects of ATM and ATR inhibition in combination with radiotherapy in prostate cancer and offers opportunities for exploring the use of radiotherapy and immunotherapy combinations in mCRPC.