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

Michal Smida, Ferran Fece de la Cruz, Claudia Kerzendorfer, Iris Z. Uras, Barbara Mair, Abdelghani Mazouzi, Tereza Suchankova, Tomasz Konopka, Amanda M. Katz, Keren Paz, Katalin Nagy-Bojarszky, Markus K. Muellner, Zsuzsanna Bago-Horvath, Eric B. Haura, Joanna I. Loizou and Sebastian M. B. Nijman ()
Additional contact information
Michal Smida: Research Center for Molecular Medicine of the Austrian Academy of Sciences (CeMM)
Ferran Fece de la Cruz: Research Center for Molecular Medicine of the Austrian Academy of Sciences (CeMM)
Claudia Kerzendorfer: Research Center for Molecular Medicine of the Austrian Academy of Sciences (CeMM)
Iris Z. Uras: Research Center for Molecular Medicine of the Austrian Academy of Sciences (CeMM)
Barbara Mair: Research Center for Molecular Medicine of the Austrian Academy of Sciences (CeMM)
Abdelghani Mazouzi: Research Center for Molecular Medicine of the Austrian Academy of Sciences (CeMM)
Tereza Suchankova: Academy of Sciences of the Czech Republic, Institute of Biophysics
Tomasz Konopka: Research Center for Molecular Medicine of the Austrian Academy of Sciences (CeMM)
Amanda M. Katz: Champions Oncology
Keren Paz: Champions Oncology
Katalin Nagy-Bojarszky: Research Center for Molecular Medicine of the Austrian Academy of Sciences (CeMM)
Markus K. Muellner: Research Center for Molecular Medicine of the Austrian Academy of Sciences (CeMM)
Zsuzsanna Bago-Horvath: Institute of Pharmacology and Toxicology, University of Veterinary Medicine
Eric B. Haura: H. Lee Moffitt Cancer Center and Research Institute
Joanna I. Loizou: Research Center for Molecular Medicine of the Austrian Academy of Sciences (CeMM)
Sebastian M. B. Nijman: Research Center for Molecular Medicine of the Austrian Academy of Sciences (CeMM)

Nature Communications, 2016, vol. 7, issue 1, 1-13

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms13701

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