ATM Loss Confers Greater Sensitivity to ATR Inhibition Than PARP Inhibition in Prostate Cancer

Abstract

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.

Integrated molecular drivers coordinate biological and clinical states in melanoma

“…Prospective assessment of genomically stratified melanomas that consider mutational signatures may enable recovery of a rarely utilized therapeutic modality (platinum-based chemotherapy) and others not widely considered (e.g. ATR inhibitors 68 , 76 ) for melanoma. Moreover, prospective generation of new melanoma models that captures the genomic and phenotypic diversity of the disease (e.g.…”

Genetic aberrations in DNA repair pathways: a cornerstone of precision oncology in prostate cancer

“…Although previous data have suggested that ATM-deficient tumours show an increased sensitivity to PARPi, 47 preclinical findings contradict these reports. 66 Clinical trials conducted in mCRPC patients have shown very limited benefit of PARPi for patients with ATM alterations. 19,[54][55][56][57][58][59] Thus, other strategies should be explored in these patients, and several ATR, ATM and Chk inhibitors either alone or in combination with other agents are at different stages of preclinical or clinical development 67,68 (Table 2).…”

The genetics of ductal adenocarcinoma of the pancreas in the year 2020: dramatic progress, but far to go

“…ATM inactivation is predicted to inhibit the repair of double-stand DNA breaks, thereby increasing genomic instability and increasing sensitivity to radiation therapy and to platinum-containing drugs, as these therapies induce double-strand breaks [93,94,98]. Although ATM mutated cells were reported to be sensitive to PARP inhibitors in vitro, studies to date have not demonstrated these drugs to be effective in genetic models or in patients with ATM mutations [99,100]. In addition, a number of compounds are now available to target the ATRcheckpoint kinase 1 (Chk1) pathway, including compounds that target ATR and Chk1 (a serine/threonine kinase functioning downstream of ATR), and pancreatic cancers with loss of ATM-mediated DNA repair may show increased sensitivity to one of these [93,94].…”