title: ATMDeficiency Is Associated with Sensitivity to PARP1- and ATR Inhibitors in Lung Adenocarcinoma.
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-allelicAtmdeletion in mouse models ofKras-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.Atmdeficiency also markedly enhanced sensitivity to the ATR inhibitor VE-822. Taken together, our results provide a functional rationale to profile human tumors for disablingATMmutations, particularly given their impact on PARP1 and ATR inhibitors.Cancer Res; 77(11); 3040-56. ©2017 AACR.
authors.affiliation: Department I of Internal Medicine, University Hospital of Cologne, Cologne, Germany. christian.reinhardt@uk-koeln.de anna.schmitt@uk-koeln.de.|Cologne Excellence Cluster on Cellular Stress Response in Aging-Associated Diseases, University of Cologne, Cologne, Germany.
authors.forename: Anna
authors.initials: A
authors.lastname: Schmitt
authors.affiliation: Department I of Internal Medicine, University Hospital of Cologne, Cologne, Germany.|Cologne Excellence Cluster on Cellular Stress Response in Aging-Associated Diseases, University of Cologne, Cologne, Germany.
authors.forename: Gero
authors.initials: G
authors.lastname: Knittel
authors.affiliation: Department I of Internal Medicine, University Hospital of Cologne, Cologne, Germany.|Cologne Excellence Cluster on Cellular Stress Response in Aging-Associated Diseases, University of Cologne, Cologne, Germany.
authors.forename: Daniela
authors.initials: D
authors.lastname: Welcker
authors.affiliation: Department of Translational Genomics, Center of Integrated Oncology Cologne-Bonn, Medical Faculty, University of Cologne, Cologne, Germany.|Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.
authors.forename: Tsun-Po
authors.initials: TP
authors.lastname: Yang
authors.affiliation: Department of Translational Genomics, Center of Integrated Oncology Cologne-Bonn, Medical Faculty, University of Cologne, Cologne, Germany.
authors.forename: Julie
authors.initials: J
authors.lastname: George
authors.affiliation: Institute of Pathology, University Hospital Bonn, Bonn, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Nowak
authors.affiliation: Department I of Internal Medicine, University Hospital of Cologne, Cologne, Germany.|Cologne Excellence Cluster on Cellular Stress Response in Aging-Associated Diseases, University of Cologne, Cologne, Germany.
authors.forename: Uschi
authors.initials: U
authors.lastname: Leeser
authors.affiliation: Institute of Pathology, University Hospital of Cologne, Cologne, Germany.
authors.forename: Reinhard
authors.initials: R
authors.lastname: Büttner
authors.affiliation: 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.
authors.forename: Sven
authors.initials: S
authors.lastname: Perner
authors.affiliation: Department of Translational Genomics, Center of Integrated Oncology Cologne-Bonn, Medical Faculty, University of Cologne, Cologne, Germany.|Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Peifer
authors.affiliation: Department I of Internal Medicine, University Hospital of Cologne, Cologne, Germany. christian.reinhardt@uk-koeln.de anna.schmitt@uk-koeln.de.|Cologne Excellence Cluster on Cellular Stress Response in Aging-Associated Diseases, University of Cologne, Cologne, Germany.|Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.
authors.forename: Hans Christian
authors.initials: HC
authors.lastname: Reinhardt
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000473:pathology; D000077192:Adenocarcinoma of Lung; D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000627:therapeutic use*; D015398:Signal Transduction
chemical_list: D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins