title: Alteration of the E-cadherin/β-catenin complex predicts poor response to epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) treatment.
abstract: BACKGROUND
  Epidermal growth factor receptor (EGFR) mutation alone may be insufficient to predict clinical outcomes in the response to EGFR-tyrosine kinase inhibitor (TKI) therapy. The secondary mutation T790 M and MET amplification are mechanisms of acquired resistance to EGFR-TKI in approximately 50 % of patients, but the remaining mechanisms are unknown.
  
  
  METHODS
  Eight metastatic lesions and specimens from 41 non-small cell lung carcinoma (NSCLC) patients harbouring activating EGFR mutations who underwent surgical resection and EGFR-TKI therapy were available. Immunohistochemistry was used to evaluate E-cadherin, β-catenin, and PTEN. Chromogenic in situ hybridisation and silver-enhanced in situ hybridisation were used to evaluate EGFR and MET amplification.
  
  
  RESULTS
  Patients with E-cadherin/β-catenin alteration showed a poor objective response rate (ORR) (p = 0.005) and shorter overall survival (p = 0.059). Additionally, β-catenin alteration was associated with a poor ORR (p = 0.012). Of the metastatic tumours, three cases (37.5 %) showed the acquisition of altered E-cadherin/β-catenin and PTEN loss and two cases (25 %) demonstrated MET/EGFR amplification.
  
  
  CONCLUSIONS
  Altered E-cadherin/β-catenin expression in NSCLC harbouring EGFR mutations was associated with a poor response to EGFR-TKI. During metastatic progression, changes in E-cadherin/β-catenin were found. These results may suggest that E-cadherin/β-catenin alteration is related to poor TKI response and resistance.
authors.affiliation: Department of Pathology, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Republic of Korea.
authors.forename: Seol Bong
authors.initials: SB
authors.lastname: Yoo
authors.forename: Yu Jung
authors.initials: YJ
authors.lastname: Kim
authors.forename: Hyojin
authors.initials: H
authors.lastname: Kim
authors.forename: Yan
authors.initials: Y
authors.lastname: Jin
authors.forename: Ping-Li
authors.initials: PL
authors.lastname: Sun
authors.forename: Sanghoon
authors.initials: S
authors.lastname: Jheon
authors.forename: Jong Seok
authors.initials: JS
authors.lastname: Lee
authors.forename: Jin-Haeng
authors.initials: JH
authors.lastname: Chung
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000378:metabolism* / Q000556:secondary; D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D015820:Cadherins / Q000378:metabolism*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000378:metabolism* / Q000556:secondary; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000378:metabolism* / Q000556:secondary; D019008:Drug Resistance, Neoplasm; D058750:Epithelial-Mesenchymal Transition; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D005260:Female; D005500:Follow-Up Studies; D018628:Gene Dosage; D006801:Humans; D007124:Immunoenzyme Techniques; D017403:In Situ Hybridization; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D011379:Prognosis; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism; D015996:Survival Rate; D046888:Tissue Array Analysis; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D014408:Biomarkers, Tumor; C495270:CTNNB1 protein, human; D015820:Cadherins; D047428:Protein Kinase Inhibitors; D051176:beta Catenin; C512478:EGFR protein, human; D066246:ErbB Receptors; C491743:MET protein, human; D011505:Protein-Tyrosine Kinases; D019859:Proto-Oncogene Proteins c-met; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human