title: MEK inhibitors block growth of lung tumours with mutations in ataxia-telangiectasia mutated.
abstract: Lung cancer is the leading cause of cancer deaths, and effective treatments are urgently needed. Loss-of-function mutations in the DNA damage response kinase ATM are common in lung adenocarcinoma but directly targeting these with drugs remains challenging. Here we report that ATM loss-of-function is synthetic lethal with drugs inhibiting the central growth factor kinases MEK1/2, including the FDA-approved drug trametinib. Lung cancer cells resistant to MEK inhibition become highly sensitive upon loss of ATM both in vitro and in vivo. Mechanistically, ATM mediates crosstalk between the prosurvival MEK/ERK and AKT/mTOR pathways. ATM loss also enhances the sensitivity of KRAS- or BRAF-mutant lung cancer cells to MEK inhibition. Thus, ATM mutational status in lung cancer is a mechanistic biomarker for MEK inhibitor response, which may improve patient stratification and extend the applicability of these drugs beyond RAS and BRAF mutant tumours.
authors.affiliation: Research Center for Molecular Medicine of the Austrian Academy of Sciences (CeMM), 1090 Vienna, Austria.|Central European Institute of Technology, Masaryk University, 62500 Brno, Czech Republic.
authors.forename: Michal
authors.initials: M
authors.lastname: Smida
authors.affiliation: Research Center for Molecular Medicine of the Austrian Academy of Sciences (CeMM), 1090 Vienna, Austria.|Nuffield Department of Clinical Medicine, Ludwig Institute for Cancer Research Ltd, University of Oxford, OX3 7FZ Oxford, UK.|Nuffield Department of Medicine, Target Discovery Institute, University of Oxford, OX3 7FZ Oxford, UK.
authors.forename: Ferran
authors.initials: F
authors.lastname: Fece de la Cruz
authors.affiliation: Research Center for Molecular Medicine of the Austrian Academy of Sciences (CeMM), 1090 Vienna, Austria.
authors.forename: Claudia
authors.initials: C
authors.lastname: Kerzendorfer
authors.affiliation: Research Center for Molecular Medicine of the Austrian Academy of Sciences (CeMM), 1090 Vienna, Austria.
authors.forename: Iris Z
authors.initials: IZ
authors.lastname: Uras
authors.affiliation: Research Center for Molecular Medicine of the Austrian Academy of Sciences (CeMM), 1090 Vienna, Austria.|Nuffield Department of Clinical Medicine, Ludwig Institute for Cancer Research Ltd, University of Oxford, OX3 7FZ Oxford, UK.|Nuffield Department of Medicine, Target Discovery Institute, University of Oxford, OX3 7FZ Oxford, UK.
authors.forename: Barbara
authors.identifier: 0000-0001-6982-2529
authors.initials: B
authors.lastname: Mair
authors.affiliation: Research Center for Molecular Medicine of the Austrian Academy of Sciences (CeMM), 1090 Vienna, Austria.
authors.forename: Abdelghani
authors.initials: A
authors.lastname: Mazouzi
authors.affiliation: Academy of Sciences of the Czech Republic, Institute of Biophysics, 61200 Brno, Czech Republic.
authors.forename: Tereza
authors.initials: T
authors.lastname: Suchankova
authors.affiliation: Research Center for Molecular Medicine of the Austrian Academy of Sciences (CeMM), 1090 Vienna, Austria.|Nuffield Department of Clinical Medicine, Ludwig Institute for Cancer Research Ltd, University of Oxford, OX3 7FZ Oxford, UK.|Nuffield Department of Medicine, Target Discovery Institute, University of Oxford, OX3 7FZ Oxford, UK.
authors.forename: Tomasz
authors.identifier: 0000-0003-3042-4712
authors.initials: T
authors.lastname: Konopka
authors.affiliation: Champions Oncology, Hackensack, New Jersey 07601, USA.
authors.forename: Amanda M
authors.initials: AM
authors.lastname: Katz
authors.affiliation: Champions Oncology, Hackensack, New Jersey 07601, USA.
authors.forename: Keren
authors.initials: K
authors.lastname: Paz
authors.affiliation: Research Center for Molecular Medicine of the Austrian Academy of Sciences (CeMM), 1090 Vienna, Austria.
authors.forename: Katalin
authors.initials: K
authors.lastname: Nagy-Bojarszky
authors.affiliation: Research Center for Molecular Medicine of the Austrian Academy of Sciences (CeMM), 1090 Vienna, Austria.
authors.forename: Markus K
authors.initials: MK
authors.lastname: Muellner
authors.affiliation: Institute of Pharmacology and Toxicology, University of Veterinary Medicine, 1210 Vienna, Austria.|Clinical Institute of Pathology, Medical University of Vienna, 1090 Vienna, Austria.
authors.forename: Zsuzsanna
authors.initials: Z
authors.lastname: Bago-Horvath
authors.affiliation: Department of Thoracic Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33612, USA.
authors.forename: Eric B
authors.initials: EB
authors.lastname: Haura
authors.affiliation: Research Center for Molecular Medicine of the Austrian Academy of Sciences (CeMM), 1090 Vienna, Austria.
authors.forename: Joanna I
authors.initials: JI
authors.lastname: Loizou
authors.affiliation: Research Center for Molecular Medicine of the Austrian Academy of Sciences (CeMM), 1090 Vienna, Austria.|Nuffield Department of Clinical Medicine, Ludwig Institute for Cancer Research Ltd, University of Oxford, OX3 7FZ Oxford, UK.|Nuffield Department of Medicine, Target Discovery Institute, University of Oxford, OX3 7FZ Oxford, UK.
authors.forename: Sebastian M B
authors.initials: SM
authors.lastname: Nijman
mesh_terms: D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins / Q000235:genetics* / Q000378:metabolism; D001549:Benzamides / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects* / Q000235:genetics; D004159:Diphenylamine / Q000031:analogs & derivatives / Q000494:pharmacology; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D008819:Mice, Nude; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics / Q000378:metabolism; D011728:Pyridones / Q000494:pharmacology; D011744:Pyrimidinones / Q000494:pharmacology; D034622:RNA Interference; D013876:Thiophenes / Q000494:pharmacology; D014508:Urea / Q000031:analogs & derivatives / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: C532363:3-(carbamoylamino)-5-(3-fluorophenyl)-N-(3-piperidyl)thiophene-2-carboxamide; D001549:Benzamides; D047428:Protein Kinase Inhibitors; D011728:Pyridones; D011744:Pyrimidinones; D013876:Thiophenes; C560077:trametinib; C506614:mirdametinib; D014508:Urea; D004159:Diphenylamine; D064007:Ataxia Telangiectasia Mutated Proteins; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D018631:ras Proteins