MEK inhibitors block growth of lung tumours with mutations in ataxia–telangiectasia mutated

• Published in: Nature communications Vol. 7; no. 1; pp. 13701 - 13
• Main Authors: Smida, Michal, Fece de la Cruz, Ferran, Kerzendorfer, Claudia, Uras, Iris Z., Mair, Barbara, Mazouzi, Abdelghani, Suchankova, Tereza, Konopka, Tomasz, Katz, Amanda M., Paz, Keren, Nagy-Bojarszky, Katalin, Muellner, Markus K., Bago-Horvath, Zsuzsanna, Haura, Eric B., Loizou, Joanna I., Nijman, Sebastian M. B.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 06.12.2016; Nature Publishing Group; Nature Portfolio
• Subjects: 13/106; 14/63; 38/109; 38/77; 631/154/1435; 631/154/53; 631/67/1612; 631/67/1857; 64/60; 82/51; 82/80; 96/1; Animals; Antigens; Ataxia; Ataxia Telangiectasia Mutated Proteins - genetics; Ataxia Telangiectasia Mutated Proteins - metabolism; Benzamides - pharmacology; Cancer therapies; Cell growth; Cell Line, Tumor; Cell Proliferation - drug effects; Cell Proliferation - genetics; Diphenylamine - analogs & derivatives; Diphenylamine - pharmacology; DNA damage; Drugs; Genes; Genomes; Growth factors; Humanities and Social Sciences; Humans; Kinases; Lung cancer; Lung Neoplasms - genetics; Lung Neoplasms - metabolism; Lung Neoplasms - prevention & control; Medical research; Medicine; Mice, Nude; multidisciplinary; Mutation; Oncology; Protein Kinase Inhibitors - pharmacology; Proto-Oncogene Proteins B-raf - genetics; Proto-Oncogene Proteins B-raf - metabolism; Pyridones - pharmacology; Pyrimidinones - pharmacology; ras Proteins - genetics; ras Proteins - metabolism; RNA Interference; Science; Science (multidisciplinary); Thiophenes - pharmacology; Tumors; Urea - analogs & derivatives; Urea - pharmacology; Xenograft Model Antitumor Assays; Czech Republic; Austria; United Kingdom > UK; United States > US
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms13701

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. ATM is a tumor suppressor often mutated in lung adenocarcinoma. In this study, the authors starting from a synthetic lethal screen, demonstrate that tumor cells with mutations in ATM exhibit increased sensitivity to MEK1/2 inhibition through the modulation of the AKT/mTOR pathway.