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.

Academy of Sciences of the Czech Republic Institute of Biophysics 61200 Brno Czech Republic

Central European Institute of Technology Masaryk University 62500 Brno Czech Republic

Champions Oncology Hackensack New Jersey 07601 USA

Clinical Institute of Pathology Medical University of Vienna 1090 Vienna Austria

Department of Thoracic Oncology H Lee Moffitt Cancer Center and Research Institute Tampa Florida 33612 USA

Institute of Pharmacology and Toxicology University of Veterinary Medicine 1210 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

Research Center for Molecular Medicine of the Austrian Academy of Sciences 1090 Vienna Austria

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