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

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