Neuroblastoma is the most common extracranial solid tumour of infancy. Pathological activation of glucose consumption, glycolysis and glycolysis-activating Akt kinase occur frequently in neuroblastoma cells, and these changes correlate with poor prognosis of patients. Therefore, several inhibitors of glucose utilization and the Akt kinase activity are in preclinical trials as potential anti-cancer drugs. However, metabolic plasticity of cancer cells might undermine efficacy of this approach. In this work, we identified oxidative phosphorylation as compensatory mechanism preserving viability of neuroblastoma cells with inhibited glucose uptake/Akt kinase. It was oxidative phosphorylation that maintained intracellular level of ATP and proliferative capacity of these cells. The oxidative phosphorylation inhibitors (rotenone, tetrathiomolybdate) synergized with inhibitor of the Akt kinase/glucose uptake in down-regulation of both viability of neuroblastoma cells and clonogenic potential of cells forming neuroblastoma spheroids. Interestingly, tetrathiomolybdate acted as highly specific inhibitor of oxygen consumption and activator of lactate production in neuroblastoma cells, but not in normal fibroblasts and neuronal cells. Moreover, the reducing effect of tetrathiomolybdate on cell viability and the level of ATP in the cells with inhibited Akt kinase/glucose uptake was also selective for neuroblastoma cells. Therefore, efficient elimination of neuroblastoma cells requires inhibition of both glucose uptake/Akt kinase and oxidative phosphorylation activities. The use of tetrathiomolybdate as a mitochondrial inhibitor contributes to selectivity of this combined treatment, preferentially targeting neuroblastoma cells.

• Klíčová slova
• Akt kinase, cell viability, glycolysis, metabolic plasticity, neuroblastoma, oxygen consumption, tetrathiomolybdate,
• MeSH
• adenosintrifosfát metabolismus   MeSH
• buněčné dýchání účinky léků   MeSH
• down regulace účinky léků   MeSH
• fibroblasty účinky léků   metabolismus   MeSH
• fosforylace účinky léků   MeSH
• glukosa metabolismus   MeSH
• inhibitory proteinkinas farmakologie   MeSH
• kyselina mléčná biosyntéza   MeSH
• lidé MeSH
• mitochondrie účinky léků   metabolismus   MeSH
• molybden farmakologie   MeSH
• myši inbrední C57BL MeSH
• nádorové buněčné linie MeSH
• neuroblastom enzymologie   metabolismus   patologie   MeSH
• neurony účinky léků   metabolismus   MeSH
• oxidativní fosforylace účinky léků   MeSH
• protoonkogenní proteiny c-akt antagonisté a inhibitory   metabolismus   MeSH
• spotřeba kyslíku účinky léků   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• adenosintrifosfát MeSH
• glukosa MeSH
• inhibitory proteinkinas MeSH
• kyselina mléčná MeSH
• molybden MeSH
• protoonkogenní proteiny c-akt MeSH
• tetrathiomolybdate MeSH Prohlížeč

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