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|Ref Type||Journal Article|
|Authors||Rafiei S, Fitzpatrick K, Liu D, Cai MY, Elmarakeby HA, Park J, Ricker C, Kochupurakkal BS, Choudhury AD, Hahn WC, Balk SP, Hwang JH, Van Allen EM, Mouw KW|
|Title||ATM Loss Confers Greater Sensitivity to ATR Inhibition Than PARP Inhibition in Prostate Cancer.|
|Date||2020 Jun 01|
|Abstract Text||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.See related commentary by Setton and Powell, p. 2085.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Therapy Name||Drugs||Efficacy Evidence||Clinical Trials|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|ATM del||prostate cancer||sensitive||Berzosertib||Preclinical - Cell culture||Actionable||In a preclinical study, ATM-deficient prostate cancer cell lines were sensitive to treatment with Berzosertib (VX-970) in culture, demonstrating inhibition of cell growth (PMID: 32127357).||32127357|
|ATM del||prostate cancer||no benefit||Rucaparib||Preclinical - Cell culture||Actionable||In a preclinical study, ATM-deficient prostate cancer cell lines did not respond to treatment with Rubraca (rucaparib) in culture (PMID: 32127357).||32127357|
|ATM del||prostate cancer||no benefit||Olaparib||Preclinical - Cell culture||Actionable||In a preclinical study, ATM-deficient prostate cancer cell lines did not respond to treatment with Lynparza (olaparib) in culture (PMID: 32127357).||32127357|