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Cancer Res. 2017 Jun 1;77(11):3040-3056. doi: 10.1158/0008-5472.CAN-16-3398. Epub 2017 Mar 31.

ATM Deficiency Is Associated with Sensitivity to PARP1- and ATR Inhibitors in Lung Adenocarcinoma.

Author information

1
Department I of Internal Medicine, University Hospital of Cologne, Cologne, Germany. christian.reinhardt@uk-koeln.de anna.schmitt@uk-koeln.de.
2
Cologne Excellence Cluster on Cellular Stress Response in Aging-Associated Diseases, University of Cologne, Cologne, Germany.
3
Department I of Internal Medicine, University Hospital of Cologne, Cologne, Germany.
4
Department of Translational Genomics, Center of Integrated Oncology Cologne-Bonn, Medical Faculty, University of Cologne, Cologne, Germany.
5
Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.
6
Institute of Pathology, University Hospital Bonn, Bonn, Germany.
7
Institute of Pathology, University Hospital of Cologne, Cologne, Germany.
8
Department of Pathology, University Medical Center Schleswig-Holstein, Campus Luebeck and the Research Center Borstel, Leibniz Center for Medicine and Biosciences, Luebeck and Borstel, Germany.

Abstract

Defects in maintaining genome integrity are a hallmark of cancer. The DNA damage response kinase ATM is frequently mutated in human cancer, but the significance of these events to chemotherapeutic efficacy has not been examined deeply in whole organism models. Here we demonstrate that bi-allelic Atm deletion in mouse models of Kras-mutant lung adenocarcinoma does not affect cisplatin responses. In marked contrast, Atm-deficient tumors displayed an enhanced response to the topoisomerase-II poison etoposide. Moreover, Atm-deficient cells and tumors were sensitive to the PARP inhibitor olaparib. This actionable molecular addiction to functional PARP1 signaling was preserved in models that were proficient or deficient in p53, resembling standard or high-risk genetic constellations, respectively. Atm deficiency also markedly enhanced sensitivity to the ATR inhibitor VE-822. Taken together, our results provide a functional rationale to profile human tumors for disabling ATM mutations, particularly given their impact on PARP1 and ATR inhibitors. Cancer Res; 77(11); 3040-56. ©2017 AACR.

PMID:
28363999
DOI:
10.1158/0008-5472.CAN-16-3398
[Indexed for MEDLINE]
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