title: MET-EGFR dimerization in lung adenocarcinoma is dependent on EGFR mtations and altered by MET kinase inhibition.
abstract: 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.
authors.affiliation: Division of Asthma, Allergy and Lung Biology, King's College London, Guy's Hospital, London, United Kingdom.
authors.forename: Elena
authors.initials: E
authors.lastname: Ortiz-Zapater
authors.affiliation: Division of Asthma, Allergy and Lung Biology, King's College London, Guy's Hospital, London, United Kingdom.
authors.forename: Richard W
authors.initials: RW
authors.lastname: Lee
authors.affiliation: Division of Asthma, Allergy and Lung Biology, King's College London, Guy's Hospital, London, United Kingdom.
authors.forename: William
authors.initials: W
authors.lastname: Owen
authors.affiliation: Richard Dimbleby Department of Cancer Research, Randall Division of Cell and Molecular Biophysics, King's College London, Guy's Medical School Campus, London, United Kingdom.
authors.forename: Gregory
authors.initials: G
authors.lastname: Weitsman
authors.affiliation: Department of Imaging Chemistry and Biology, Division of Imaging Science and Biomedical Engineering, King's College London, The Rayne Institute/St. Thomas' Hospital, London, United Kingdom.
authors.forename: Gilbert
authors.initials: G
authors.lastname: Fruhwirth
authors.affiliation: Department of Cancer Genetics, Viapath, Guy's and St Thomas' NHS Foundation Trust, Guy's Hospital, London, United Kingdom.
authors.forename: Robert G
authors.initials: RG
authors.lastname: Dunn
authors.affiliation: Department of Cancer Genetics, Viapath, Guy's and St Thomas' NHS Foundation Trust, Guy's Hospital, London, United Kingdom.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Neat
authors.affiliation: Division of Asthma, Allergy and Lung Biology, King's College London, Guy's Hospital, London, United Kingdom.
authors.forename: Frank
authors.initials: F
authors.lastname: McCaughan
authors.affiliation: Division of Cancer Studies, King's College London, Guy's Medical School Campus, London, United Kingdom.|Protein Phosphorylation Laboratory, Francis Crick Institute, London, United Kingdom.
authors.forename: Peter
authors.initials: P
authors.lastname: Parker
authors.affiliation: Richard Dimbleby Department of Cancer Research, Randall Division of Cell and Molecular Biophysics, King's College London, Guy's Medical School Campus, London, United Kingdom.|Division of Cancer Studies, King's College London, Guy's Medical School Campus, London, United Kingdom.|Breast Cancer Research Unit, King's College London, Guy's Hospital, London, United Kingdom.|UCL Cancer Institute, Paul O' Gorman Building, University College London, London, United Kingdom.
authors.forename: Tony
authors.initials: T
authors.lastname: Ng
authors.affiliation: Division of Asthma, Allergy and Lung Biology, King's College London, Guy's Hospital, London, United Kingdom.
authors.forename: George
authors.initials: G
authors.lastname: Santis
mesh_terms: D000230:Adenocarcinoma / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D000077192:Adenocarcinoma of Lung; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D066246:ErbB Receptors / Q000235:genetics*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009154:Mutation / Q000235:genetics*; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D055503:Protein Multimerization / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015203:Reproducibility of Results
chemical_list: D047428:Protein Kinase Inhibitors; D066246:ErbB Receptors; D019859:Proto-Oncogene Proteins c-met; D051416:Focal Adhesion Protein-Tyrosine Kinases; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases