Reference Detail

Ref Type

Journal Article

PMID

(32127357)

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.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Cancer research	80	11	2020 Jun 01	2094-2100	Cancer Res

URL

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.

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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	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
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