Targeting nuclear HER3-AKT cascade improves radiotherapy of non-small cell lung cancer

Background: Double-strand breaks (DSB) are the most lethal type of DNA damage induced by ionizing radiation (IR) that repaired either non-homologous end joining (NHEJ) throughout cell cycle or homologous recombination (HR) during S phase and G2 phase. The repair IR-induced DSB through NHEJ HR is partially dependent on AKT. AKT must be present activated in nucleus immediately after irradiation to initiate described fast process. We investigated subcellular distribution AKT1 IR role epidermal growth factor receptor (EGFR)/HER family members activation nuclear AKT1. Materials methods: Plasmid-based overexpression siRNA transfections as well pharmacological inhibitors were applied analyze HER phosphorylation non-small lung cancer (NSCLC) cells vitro. γH2AX foci assay was investigate activating signaling pathway repair. A mouse tumor NSCLC xenograft model used study impact response vivo. Results: GFP-tagged exogenous (GFP-AKT1) detected 24 h transfection accumulation not modified IR. Nuclear translocation GFP-AKT1 inhibited phosphatidylinositol 3-kinase HER3 ligand endogenous levels both fractions. Activation these stimuli associated with primarily expression EGFR tyrosine kinase activity. In line repair, neutralizing antibody patritumab HER3-siRNA diminished Combination radiotherapy improved effect delay a model. Conclusions: occurs mainly NSCLC. Thus, targeting combination may provide logical treatment option for investigation selected patients. No conflict interest.