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

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Authors

ŠMÍDA Michal DE LA CRUZ Ferran Fece 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.

Year of publication 2016
Type Article in Periodical
Magazine / Source Nature Communications
MU Faculty or unit

Central European Institute of Technology

Citation
web http://www.nature.com/articles/ncomms13701
Doi http://dx.doi.org/10.1038/ncomms13701
Field Oncology and hematology
Keywords BREAST-CANCER; INSULIN-RESISTANCE; MISSENSE MUTATIONS; DNA-DAMAGE; ATM; AUTOPHAGY; VARIANTS; PATHWAYS; MTORC1; CELLS
Description 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.
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