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

Varování

Publikace nespadá pod Fakultu sportovních studií, ale pod Středoevropský technologický institut. Oficiální stránka publikace je na webu muni.cz.

Autoři	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.
Rok publikování	2016
Druh	Článek v odborném periodiku
Časopis / Zdroj	Nature Communications
Fakulta / Pracoviště MU	Středoevropský technologický institut
Citace
www	http://www.nature.com/articles/ncomms13701
Doi	http://dx.doi.org/10.1038/ncomms13701
Obor	Onkologie a hematologie
Klíčová slova	BREAST-CANCER; INSULIN-RESISTANCE; MISSENSE MUTATIONS; DNA-DAMAGE; ATM; AUTOPHAGY; VARIANTS; PATHWAYS; MTORC1; CELLS
Popis	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.
Související projekty:	CEITEC 2020