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

Warning

This publication doesn't include Faculty of Sports Studies. It includes Central European Institute of Technology. Official publication website can be found on muni.cz.

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.
Related projects:	CEITEC 2020