ATM loss confers greater sensitivity to ATR inhibition than PARP inhibition in prostate cancer

Alterations in DNA damage response (DDR) genes are common in advanced prostate tumors and are associated with unique genomic and clinical features. ATM is a DDR kinase that has a central role in coordinating DNA repair and cell-cycle response following DNA damage, and ATM alterations are present in approximately 5% of advanced prostate tumors. Recently, inhibitors of PARP have demonstrated activity in advanced prostate tumors harboring DDR gene alterations, particularly in tumors with BRCA1/2 alterations. However, the role of alterations in DDR genes beyond BRCA1/2 in mediating PARP inhibitor sensitivity is poorly understood. To define the role of ATM loss in prostate tumor DDR function and sensitivity to DDR-directed agents, we created a series of ATM-deficient preclinical prostate cancer models and tested the impact of ATM loss on DNA repair function and therapeutic sensitivities. ATM loss altered DDR signaling, but did not directly impact homologou recombination function. Furthermore, ATM loss did not significant ly impact sensitivity to PARP inhibition but robustly sensitized t inhibitors of the related DDR kinase ATR. These results hav important implications for planned and ongoing prostate cance clinical trials and suggest that patients with tumor ATM alteration may be more likely to benefit from ATR inhibitor than PAR inhibitor therapy.