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 homologous recombination function. Furthermore, ATM loss did not significantly impact sensitivity to PARP inhibition but robustly sensitized to inhibitors of the related DDR kinase ATR. These results have important implications for planned and ongoing prostate cancer clinical trials and suggest that patients with tumor ATM alterations may be more likely to benefit from ATR inhibitor than PARP inhibitor therapy.Significance: ATM loss occurs in a subset of prostate tumors. This study shows that deleting ATM in prostate cancer models does not significantly increase sensitivity to PARP inhibition but does sensitize to ATR inhibition.

<p>Immunofluorescence and IR survival data; additional methods</p>

<p>siRNA and sgRNA sequences</p>

<div>Abstract<p>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 <i>ATM</i> 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 <i>BRCA1/2</i> alterations. However, the role of alterations in DDR genes beyond <i>BRCA1/2</i> in mediating PARP inhibitor sensitivity is poorly understood. To define the role of <i>ATM</i> loss in prostate tumor DDR function and sensitivity to DDR-directed agents, we created a series of <i>ATM</i>-deficient preclinical prostate cancer models and tested the impact of <i>ATM</i> loss on DNA repair function and therapeutic sensitivities. <i>ATM</i> loss altered DDR signaling, but did not directly impact homologous recombination function. Furthermore, <i>ATM</i> loss did not significantly impact sensitivity to PARP inhibition but robustly sensitized to inhibitors of the related DDR kinase ATR. These results have important implications for planned and ongoing prostate cancer clinical trials and suggest that patients with tumor <i>ATM</i> alterations may be more likely to benefit from ATR inhibitor than PARP inhibitor therapy.</p>Significance:<p>ATM loss occurs in a subset of prostate tumors. This study shows that deleting ATM in prostate cancer models does not significantly increase sensitivity to PARP inhibition but does sensitize to ATR inhibition.</p><p><i>See related commentary by Setton and Powell, p. 2085</i></p></div>