Lung cancer is the leading cause of cancer deaths in the world. More than 85% of these cases are classified as Non small cell lung cancer (NSCLC) which has a dismal 5-year survival rate of 15% in addition to which most patients are diagnosed at an advance stage. Receptor tyrosine kinases are high affinity cell surface receptors that are often deregulated in a host of cancers including NSCLC thereby making them attractive targets. RTK inhibitors in the market however are facing the growing problem of resistance owing to compensatory kinases that compensate for the loss of the original oncogenic driver receptor. While attempting to identify compensatory kinases in NSCLC cell lines we observed a unique interaction between three RTKs- the Fibroblast growth factor receptor 3 (FGFR3), the Epidermal growth factor (EGFR) and mesenchymal epidermal transition (c-Met). We were able to show that upon inhibition of FGFR3 by a small molecule pan FGFR inhibitor LY2874455 there was complete attenuation of c-Met phosphorylation. Previous studies and our own observations led us to believe that c-Met activation occurred in a ligand independent manner which has previously been shown to be mediated by EGFR. EGFR phosphorylation was decreased on treatment with LY 2874455 along with a subsequent decrease in the levels of the EGFR ligand- Amphiregulin. The combined effect of LY2874455 with a c-Met inhibitor, Crizotinib, showed increased cell death as compared to either drug alone. This interaction was seen in the FGFR1 non amplified cell lines thereby suggesting that the use of this FGFR based therapy can be used in patients lacking the said amplification. We therefore have substantial evidence linking the FGFR3, EGFR and c-Met pathways suggesting that inhibition of FGFR3 inhibits the ligand independent activation of c-Met as regulated by EGFR.
University of Minnesota M.S. thesis. July 2016. Major: Pharmacology. Advisor: Jill Siegfried. 1 computer file (PDF); v, 45 pages.
FGFR3 Regulates EGFR Mediated Ligand Independent Activation Of C-Met In Non Small Cell Lung Cancer.
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