Dataset Information

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.See related commentary by Setton and Powell, p. 2085.

SUBMITTER: Rafiei S

PROVIDER: S-EPMC7272301 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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

Rafiei Shahrzad S Fitzpatrick Kenyon K Liu David D Cai Mu-Yan MY Elmarakeby Haitham A HA Park Jihye J Ricker Cora C Kochupurakkal Bose S BS Choudhury Atish D AD Hahn William C WC Balk Steven P SP Hwang Justin H JH Van Allen Eliezer M EM Mouw Kent W KW

Cancer research 20200303 11

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 ...[more]

PMID: 32127357

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Project description:Abstract Paediatric high grade glioma (pHGG) are defined by recurrent mutations in H3 histones, as well as frequent alterations in the SWI/SNF chromatin remodelling gene ATRX (α-thalassemia mental retardation X-linked), although the precise role of ATRX in tumorigenesis remains unclear. We sought to explore this using genomic analysis of patient samples, CRISPR-Cas9 engineered isogenic ATRX knockout (KO) cell lines and primary-patient-derived cultures. In combined retrospective and prospective cohorts of pHGG samples, we found ATRX mutations in 95/510 (18.6%) cases (27% hemispheric glioblastoma, 13% diffuse midline glioma), with the majority of truncating mutations found in the ADD domain, and missense mutations almost exclusively in the helicase domain. ATRX mutations commonly co-segregate with H3.3G34 and TP53 mutations, and define a subgroup of patients with a longer overall survival, though with a greater number of somatic mutations and copy number alterations than wild-type cases. CRISPR/Cas9-mediated ATRX KO targeting the ADD domain in TP53 mutant paediatric glioblastoma cells lead to loss of imprinting at the H19 locus in concert with upregulation of a pro-invasive transcriptional programme, though a slower rate of orthotopic tumour growth in vivo. ATRX deficient cells showed an abrogated DNA damage response, with prolonged accumulation of gH2AX foci after irradiation, and an increased dependency on PARP1 through persistent parylation and stalled replication forks. Screening ATRX-deficient isogenics and patient-derived cells against a library of >400 chemotherapeutics and small molecules identified a specific dependency for ATRX loss and sensitivity to distinct PARP inhibitor chemotypes, including catalytic inhibitors (olaparib, rucaparib), and PARP trappers (talazoparib). ATRX deficiency further conferred an enhanced radiosensitization of olaparib in vitro and a prolonged survival of mice treated with combined PARP inhibition and radiotherapy in vivo. These data suggest a synthetic lethality for PARP inhibitors in ATRX-deficient pHGG, and may represent a novel therapeutic strategy for these highly aggressive tumours.

Dataset Information

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

Publications

<i>ATM</i> Loss Confers Greater Sensitivity to ATR Inhibition Than PARP Inhibition in Prostate Cancer.

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