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.

• MeSH
• ATM protein genetika   metabolismus   MeSH
• benzamidy farmakologie   MeSH
• difenylamin analogy a deriváty   farmakologie   MeSH
• inhibitory proteinkinas farmakologie   MeSH
• lidé MeSH
• močovina analogy a deriváty   farmakologie   MeSH
• mutace * MeSH
• myši nahé MeSH
• nádorové buněčné linie MeSH
• nádory plic genetika   metabolismus   prevence a kontrola   MeSH
• proliferace buněk účinky léků   genetika   MeSH
• protoonkogenní proteiny B-Raf genetika   metabolismus   MeSH
• pyridony farmakologie   MeSH
• pyrimidinony farmakologie   MeSH
• Ras proteiny genetika   metabolismus   MeSH
• RNA interference MeSH
• thiofeny farmakologie   MeSH
• xenogenní modely - testy antitumorózní aktivity MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• 3-(carbamoylamino)-5-(3-fluorophenyl)-N-(3-piperidyl)thiophene-2-carboxamide MeSH Prohlížeč
• ATM protein MeSH
• benzamidy MeSH
• BRAF protein, human MeSH Prohlížeč
• difenylamin MeSH
• inhibitory proteinkinas MeSH
• mirdametinib MeSH Prohlížeč
• močovina MeSH
• protoonkogenní proteiny B-Raf MeSH
• pyridony MeSH
• pyrimidinony MeSH
• Ras proteiny MeSH
• thiofeny MeSH
• trametinib MeSH Prohlížeč