Exploring EGFR and MET cross-talk in NSCLC: a pathway to improved therapy efficacy

Non-small cell lung cancer (NSCLC) is a major global cause of cancer-related deaths. Targeted therapies like epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) can extend survival in NSCLC patients, but their effects are temporary. The MET receptor, which binds to hepatocyte growth factor (HGF), has been linked to EGFR-TKI resistance, but the mechanisms behind this are not fully known. We studied how EGF and HGF signals are transmitted in different NSCLC cell lines, which have varying levels and mutations of EGFR and MET. We first used immunoblotting to generate data, which showed that upon co-stimulation with EGF and HGF the receptors" phosphorylation was in one of the cell lines prolonged due to synergistic effects. Mass-spectrometry (MS) based phosphoproteomics using data independent acquisition confirmed this prolonged receptor phosphorylation in certain conditions and revealed further downstream communication, such as prolonged phosphorylation of mitogen-activated protein kinase (MAPK) pathway members. Furthermore, co-stimulation with EGF and HGF resulted in a sustained receptor half-life which influences downstream signaling behavior. We confirmed the hypothesis of receptor interaction using fluorescent live-cell microscopy, retroviral transduction, and siRNA knockdown of the receptors. Our dynamic pathway model indicated that a high receptor ratio could enhance the effectiveness of EGFR-TKIs. We are currently analyzing preliminary tissue samples from NSCLC patients treated with EGFR-TKIs to validate the abundance and phosphorylation of the receptors in primary samples. In conclusion, our findings suggest a strategy to potentially enhance the efficacy of EGFR and MET-targeting treatments.