Use this URL to cite or link to this record in EThOS: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.733339
Title: MET-EGFR dimerisation in lung adenocarcinoma is dependent on EGFR mutations and altered by MET kinase inhibition
Author: Lee, Richard William
ISNI:       0000 0004 6497 6985
Awarding Body: King's College London
Current Institution: King's College London (University of London)
Date of Award: 2017
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Abstract:
Prognosis in advanced stage lung cancer is extremely poor with few effective therapies. EGFR tyrosine kinase inhibitors (TKIs) have high response rates in patients with activating EGFR mutations and are now an established part of therapy in selected patients. Such advances herald a previously unprecedented enthusiasm for the possibilities of targeted therapy. Acquired resistance however is widespread - the EGFR T790M mutation in particular represents approximately 50% of these. MET amplification is also an important route of resistance and preclinical data suggests synergy between therapies targeting these two receptors. We hypothesized that EGFR mutation status determines the EGFR-MET interaction and response to MET inhibition. We tested this hypothesis by using cells derived from NCI-H1975, which possess L858R and T790M EGFR mutations. This cell model and a derived murine xenograft experiment provided a platform with which to test these ideas by using assays of tumorigenicity in vitro; tumour growth/stroma formation in vivo and a selective MET kinase inhibitor, SGX523. EGFR-MET interaction was assessed by a Förster Resonance Energy Transfer (FRET) Fluorescence Lifetime Imaging Microscopy (FLIM) assay developed as part of this thesis that quantified EGFR-MET dimer formation. SGX523 significantly reduced cell proliferation, xenograft tumour growth and ERK phosphorylation in the presence of the EGFR L858R-T790M mutations but not with EGFR L858R alone where SGX523 reduced stroma formation but not growth. SGX523 reduced EGFR-MET dimerisation in the EGFR L858R-T790M mutant but increased EGFR-MET interaction in the presence of EGFR L858R alone. Little effect was seen with EGFR WT in response to SGX523 for any of these indices. This thesis provides novel data for the mechanistic understanding of EGFR-MET heterodimerisation and the accompanying discussion explores how this is relevant for EGFR and MET targeted therapies.
Supervisor: Ng, Tony Tsz-cheong ; Santis, George Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.733339  DOI: Not available
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