MET-EGFR dimerization in lung adenocarcinoma is dependent on EGFR mtations and altered by MET kinase inhibition

6533b854fe1ef96bd12ae23e

RESEARCH PRODUCT

MET-EGFR dimerization in lung adenocarcinoma is dependent on EGFR mtations and altered by MET kinase inhibition

Richard W J Lee Elena Ortiz-zapater George Santis Tony Ng Frank Mccaughan Michael J. Neat Gilbert O. Fruhwirth Gregory Weitsman Peter J. Parker W. Owen Robert G Dunn

subject

0301 basic medicine Lung Neoplasms Kinase Inhibitors Cancer Treatment lcsh:Medicine Physical Chemistry Biochemistry Fluorophotometry T790M Spectrum Analysis Techniques 0302 clinical medicine Fluorescence Resonance Energy Transfer Medicine and Health Sciences Phosphorylation Enzyme Inhibitors lcsh:Science Extracellular Signal-Regulated MAP Kinases EGFR inhibitors Staining Mice Inbred BALB C Multidisciplinary Fluorescent in Situ Hybridization Physics Cell Staining Proto-Oncogene Proteins c-met Precipitation Techniques ErbB Receptors Chemistry Oncology Spectrophotometry 030220 oncology & carcinogenesis Physical Sciences Erlotinib Dimerization Protein Binding Research Article medicine.drug Chemical physics Mice Nude Molecular Probe Techniques Adenocarcinoma of Lung Adenocarcinoma Biology Research and Analysis Methods 03 medical and health sciences Gefitinib Growth factor receptor Cell Line Tumor medicine Animals Humans Immunoprecipitation Molecular Biology Techniques Lung cancer Protein Kinase Inhibitors Molecular Biology Cell Proliferation Cell growth lcsh:R Reproducibility of Results Biology and Life Sciences Dimers (Chemical physics)medicine.disease Molecular biology Isogenic human disease models Probe Hybridization respiratory tract diseases HEK293 Cells 030104 developmental biology Chemical Properties Specimen Preparation and Treatment Focal Adhesion Protein-Tyrosine Kinases Mutation Enzymology lcsh:Q Protein Multimerization Proto-Oncogene Proteins c-akt Cytogenetic Techniques

description

Advanced lung cancer has poor survival with few therapies. EGFR tyrosine kinase inhibitors (TKIs) have high response rates in patients with activating EGFR mutations, but acquired resistance is inevitable. Acquisition of the EGFR T790M mutation causes over 50% of resistance; MET amplification is also common. Preclinical data suggest synergy between MET and EGFR inhibitors. We hypothesized that EGFR-MET dimerization determines response to MET inhibition, depending on EGFR mutation status, independently of MET copy number. We tested this hypothesis by generating isogenic cell lines from NCI-H1975 cells, which co-express L858R and T790M EGFR mutations, namely H1975L858R/T790M (EGFR TKI resistant); H1975L858R (sensitized) and H1975WT (wild-type). We assessed cell proliferation in vitro and tumor growth/stroma formation in derived xenograft models in response to a MET TKI (SGX523) and correlated with EGFR-MET dimerization assessed by Förster Resonance Energy Transfer (FRET). SGX523 significantly reduced H1975L858R/T790M cell proliferation, xenograft tumor growth and decreased ERK phosphorylation. The same was not seen in H1975L858R or H1975WT cells. SGX523 only reduced stroma formation in H1975L858R. SGX523 reduced EGFR-MET dimerization in H1975L858R/T790M but induced dimer formation in H1975L858R with no effect in H1975WT. Our data suggests that MET inhibition by SGX523 and EGFR-MET heterodimerisation are determined by EGFR genotype. As tumor behaviour is modulated by this interaction, this could determine treatment efficacy.

year	journal	country	edition	language
2017-01-31	PLOS ONE

https://doi.org/10.1371/journal.pone.0170798