title: Met activation in non-small cell lung cancer is associated with de novo resistance to EGFR inhibitors and the development of brain metastasis.
abstract: Most non-small cell lung cancer (NSCLC) patients harboring activating epidermal growth factor receptor (EGFR) mutations respond to tyrosine kinase inhibitor (TKI) therapy. However, about 30% exhibit primary resistance to EGFR TKI therapy. Here we report that Met protein expression and phosphorylation were associated with primary resistance to EGFR TKI therapy in NSCLC patients harboring EGFR mutations, implicating Met as a de novo mechanism of resistance. In a separate patient cohort, Met expression and phosphorylation were also associated with development of NSCLC brain metastasis and were selectively enriched in brain metastases relative to paired primary lung tumors. A similar metastasis-specific activation of Met occurred in vitro in the isogenous cell lines H2073 and H1993, which are derived from the primary lung tumor and a metastasis, respectively, from the same patient. We conclude that Met activation is found in NSCLC before EGFR-targeted therapy and is associated with both primary resistance to EGFR inhibitor therapy and with the development of metastases. If confirmed in larger cohorts, our analysis suggests that patient tumors harboring both Met activation and EGFR mutation could potentially benefit from early intervention with a combination of EGFR and Met inhibitors.
authors.affiliation: Department of Medical Oncology, the Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute, Boston Massachusetts, USA.
authors.forename: Elisa
authors.initials: E
authors.lastname: Benedettini
authors.forename: Lynette M
authors.initials: LM
authors.lastname: Sholl
authors.forename: Michael
authors.initials: M
authors.lastname: Peyton
authors.forename: John
authors.initials: J
authors.lastname: Reilly
authors.forename: Christopher
authors.initials: C
authors.lastname: Ware
authors.forename: Lenora
authors.initials: L
authors.lastname: Davis
authors.forename: Natalie
authors.initials: N
authors.lastname: Vena
authors.forename: Dyane
authors.initials: D
authors.lastname: Bailey
authors.forename: Beow Y
authors.initials: BY
authors.lastname: Yeap
authors.forename: Michelangelo
authors.initials: M
authors.lastname: Fiorentino
authors.forename: Azra H
authors.initials: AH
authors.lastname: Ligon
authors.forename: Bo-Sheng
authors.initials: BS
authors.lastname: Pan
authors.forename: Victoria
authors.initials: V
authors.lastname: Richon
authors.forename: John D
authors.initials: JD
authors.lastname: Minna
authors.forename: Adi F
authors.initials: AF
authors.lastname: Gazdar
authors.forename: Giulio
authors.initials: G
authors.lastname: Draetta
authors.forename: Silvano
authors.initials: S
authors.lastname: Bosari
authors.forename: Lucian R
authors.initials: LR
authors.lastname: Chirieac
authors.forename: Bart
authors.initials: B
authors.lastname: Lutterbach
authors.forename: Massimo
authors.initials: M
authors.lastname: Loda
mesh_terms: D001932:Brain Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000556:secondary*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D019008:Drug Resistance, Neoplasm; D004789:Enzyme Activation; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics; D005260:Female; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics / Q000378:metabolism*; D015996:Survival Rate
chemical_list: D047428:Protein Kinase Inhibitors; D066246:ErbB Receptors; D019859:Proto-Oncogene Proteins c-met