title: Genomic and Molecular Screenings Identify Different Mechanisms for Acquired Resistance to MET Inhibitors in Lung Cancer Cells.
abstract: The development of resistance to tyrosine kinase inhibitors (TKI) limits the long-term efficacy of cancer treatments involving them. We aimed to understand the mechanisms that underlie acquired resistance (AR) to MET inhibitors in lung cancer. EBC1 cells, which haveMETamplification and are sensitive to TKIs against MET, were used to generate multiple clones with AR to a MET-TKI. Whole-exome sequencing, RNA sequencing, and global DNA methylation analysis were used to scrutinize the genetic and molecular characteristics of the resistant cells. AR to the MET-TKI involved changes common to all resistant cells, that is, phenotypic modifications, specific changes in gene expression, and reactivation of AKT, ERK, and mTOR. The gene expression, global DNA methylation, and mutational profiles distinguished at least two groups of resistant cells. In one of these, the cells have acquired sensitivity to erlotinib, concomitantly with mutations of theKIRREL, HDAC11, HIATL1, andMAPK1IP1Lgenes, among others. In the other group, some cells have acquired inactivation of neurofibromatosis type 2 (NF2) concomitantly with strong overexpression ofNRG1and a mutational profile that includes changes inLMLNandTOMM34Multiple independent and simultaneous strategies lead to AR to the MET-TKIs in lung cancer cells. The acquired sensitivity to erlotinib supports the known crosstalk between MET and the HER family of receptors. For the first time, we show inactivation ofNF2during acquisition of resistance to MET-TKI that may explain the refractoriness to erlotinib in these cells.Mol Cancer Ther; 16(7); 1366-76. ©2017 AACR.
authors.affiliation: Genes and Cancer Group, Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute-IDIBELL, Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: Pol
authors.initials: P
authors.lastname: Gimenez-Xavier
authors.affiliation: Genes and Cancer Group, Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute-IDIBELL, Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: Eva
authors.initials: E
authors.lastname: Pros
authors.affiliation: Genes and Cancer Group, Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute-IDIBELL, Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: Ester
authors.initials: E
authors.lastname: Bonastre
authors.affiliation: Cancer Epigenetics Group, Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute-IDIBELL, Barcelona, Spain.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Moran
authors.affiliation: Genes and Cancer Group, Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute-IDIBELL, Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Aza
authors.affiliation: Bioinformatics Unit, Structural Biology and BioComputing Programme, Spanish National Cancer Centre (CNIO), Madrid, Spain.
authors.forename: Osvaldo
authors.initials: O
authors.lastname: Graña
authors.affiliation: Bioinformatics Unit, Structural Biology and BioComputing Programme, Spanish National Cancer Centre (CNIO), Madrid, Spain.
authors.forename: Gonzalo
authors.initials: G
authors.lastname: Gomez-Lopez
authors.affiliation: CNAG-CRG, Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology (BIST), Barcelona, Spain.|Universitat Pompeu Fabra (UPF), Barcelona, Spain.
authors.forename: Sophia
authors.initials: S
authors.lastname: Derdak
authors.affiliation: CNAG-CRG, Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology (BIST), Barcelona, Spain.|Universitat Pompeu Fabra (UPF), Barcelona, Spain.
authors.forename: Marc
authors.initials: M
authors.lastname: Dabad
authors.affiliation: CNAG-CRG, Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology (BIST), Barcelona, Spain.|Universitat Pompeu Fabra (UPF), Barcelona, Spain.
authors.forename: Anna
authors.initials: A
authors.lastname: Esteve-Codina
authors.affiliation: Cancer Epigenetics Group, Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute-IDIBELL, Barcelona, Spain.
authors.forename: Jose R
authors.initials: JR
authors.lastname: Hernandez Mora
authors.affiliation: Genes and Cancer Group, Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute-IDIBELL, Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: Diana
authors.initials: D
authors.lastname: Salinas-Chaparro
authors.affiliation: Cancer Epigenetics Group, Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute-IDIBELL, Barcelona, Spain.|Institucio Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain.
authors.forename: Manel
authors.initials: M
authors.lastname: Esteller
authors.affiliation: Bioinformatics Unit, Structural Biology and BioComputing Programme, Spanish National Cancer Centre (CNIO), Madrid, Spain.
authors.forename: David
authors.initials: D
authors.lastname: Pisano
authors.affiliation: Genes and Cancer Group, Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute-IDIBELL, Hospitalet de Llobregat, Barcelona, Spain. mscespedes@idibell.cat.
authors.forename: Montse
authors.initials: M
authors.lastname: Sanchez-Cespedes
mesh_terms: D049109:Cell Proliferation / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D000069347:Erlotinib Hydrochloride / Q000008:administration & dosage; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D023281:Genomics; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D009154:Mutation; D025581:Neurofibromin 2 / Q000235:genetics*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors / Q000235:genetics*
chemical_list: D025581:Neurofibromin 2; D047428:Protein Kinase Inhibitors; D000069347:Erlotinib Hydrochloride; D019859:Proto-Oncogene Proteins c-met