title: Cetuximab Inhibits T790M-Mediated Resistance to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor in a Lung Adenocarcinoma Patient-Derived Xenograft Mouse Model.
abstract: The epidermal growth factor receptor (EGFR) kinase domain T790M (amino acid substitution at position 790 in EGFR from threonine [T] to methionine [M]) mutation in non-small-cell lung cancer (NSCLC) results in resistance to EGFR tyrosine kinase inhibitors (TKIs). We used a patient-derived tumor xenograft (PDX) model containing an EGFR exon 19 deletion/T790M mutation to assess response to the EGFR-directed antibody cetuximab. Changes in the EGFR signaling pathway and ligand expression after treatment were investigated.
  
  
  
  PDX were randomized into control and treatment arms. Pharmacodynamic studies were performed at 2 and 24 hours and at 4 days after a single administration of cetuximab, erlotinib, or dacomitinib. Changes in the EGFR signaling pathway were assessed using Western blot analysis, and baseline mRNA expression of EGFR ligands using microarray analysis. Relative changes after treatment were assessed using quantitative polymerase chain reaction.
  
  
  
  The xenograft showed a dramatic response to cetuximab. A complete reduction of total EGFR and phosphorylated EGFR occurred after cetuximab treatment. The PDX had increased baseline levels of heparin-binding epidermal growth factor-like growth factor (HB-EGF) compared with other PDX models with or without EGFR mutations. Amphiregulin was significantly reduced 2 hours after treatment with cetuximab. Compared with control mice, cetuximab- and EGFR-TKI-treated mice had significantly reduced HB-EGF gene expression at 2 hours, however, by day 4 the level of HB-EGF expression was higher. The effect of cetuximab compared with EGFR TKI on HB-EGF gene expression levels differed significantly at 2 and 24 hours but not at 4 days.
  
  
  
  We showed a dramatic tumor response with cetuximab in an exon 19 deletion/T790M EGFR mutant lung adenocarcinoma PDX model, which suggests a role for the autocrine feedback loop in the mutant EGFR signaling pathway. Further investigation using cetuximab in NSCLC with T790M mutation is warranted.
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada; Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Petra
authors.initials: P
authors.lastname: Martin
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada; Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Erin
authors.initials: E
authors.lastname: Stewart
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
authors.forename: Nhu-An
authors.initials: NA
authors.lastname: Pham
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada; Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Celine
authors.initials: C
authors.lastname: Mascaux
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
authors.forename: Devang
authors.initials: D
authors.lastname: Panchal
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
authors.forename: Ming
authors.initials: M
authors.lastname: Li
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
authors.forename: Lucia
authors.initials: L
authors.lastname: Kim
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Shingo
authors.initials: S
authors.lastname: Sakashita
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
authors.forename: Dennis
authors.initials: D
authors.lastname: Wang
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
authors.forename: Jenna
authors.initials: J
authors.lastname: Sykes
authors.affiliation: Department of Pharmacology, Roche Diagnostics GmbH, Mannheim, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Friess
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada; Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Frances A
authors.initials: FA
authors.lastname: Shepherd
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada; Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Liu
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada; Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada. Electronic address: Ming.Tsao@uhn.ca.
authors.forename: Ming-Sound
authors.initials: MS
authors.lastname: Tsao
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000473:pathology; D000077192:Adenocarcinoma of Lung; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000473:pathology; D000068818:Cetuximab / Q000008:administration & dosage; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D066246:ErbB Receptors / Q000235:genetics*; D000069347:Erlotinib Hydrochloride / Q000008:administration & dosage; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008875:Middle Aged; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D052999:Quinazolinones / Q000008:administration & dosage; D011897:Random Allocation; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D023041:Xenograft Model Antitumor Assays
chemical_list: D047428:Protein Kinase Inhibitors; D052999:Quinazolinones; C525726:dacomitinib; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors; D000068818:Cetuximab
keywords: Cancer; EGFR; Ligand; NSCLC; Signaling