Τίτλος:
EGFR-GRB2 protein colocalization is a prognostic factor unrelated to overall EGFR expression or EGFR mutation in lung adenocarcinoma
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
Introduction: EGFR is a therapeutic target in NSCLC for EGFR-mutant patients. Proximity ligation assay (PLA) is a method to detect functional signaling associated protein complexes. Growth factor receptor bound protein 2 (GRB2) is an adaptor protein that binds to the phosphorylated residues of active EGFR. Interaction of EGFR and GRB2 correlates with active EGFR signaling and leads to activation of the MAPK/ERK pathway. Methods: A PLA developed to detect EGFR-GRB2 interaction was measured by quantitative immunofluorescence using Automated Quantitative Analysis technology. EGFR pathway activation was assessed in patients with NSCLC with different mutation status along with overall EGFR expression. Additionally, the PLA to detect EGFR-GRB2 interaction was evaluated as a prognostic marker in two cohorts of patients with lung adenocarcinoma. Results: The PLA to detect EGFR-GRB2 interaction was unrelated to overall EGFR expression or mutation in a series of patients with NSCLC with known mutation status. EGFRmutant (p = 0.04) and EGFR/KRAS wild-type tumors (p = 0.0049) had significantly higher EGFR pathway activation compared with KRAS-mutant cases, with no significant difference shown between mutation sites. In two series of patients with lung adenocarcinoma, the PLA to detect EGFR-GRB2 interaction was independently associated with longer survival (hazard ratio = 0.46, 95% confidence interval: 0.2-0.78, p = 0.0085 and hazard ratio = 0.48, 95% confidence interval: 0.2-0.85, p = 0.017). Total EGFR protein expression alone was not correlated with outcome. Conclusions: EGFR colocalization with GRB2 as assessed by PLA is not correlated with EGFR expression levels or mutation status, defining a patient group that may show EGFR pathway activation, as illustrated by its prognostic value. Future studies may determine whether this group is more likely to respond to EGFR-targeted therapies. © 2016 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.
Συγγραφείς:
Toki, M.I.
Carvajal-Hausdorf, D.E.
Altan, M.
McLaughlin, J.
Henick, B.
Schalper, K.A.
Syrigos, K.N.
Rimm, D.L.
Περιοδικό:
Journal of Thoracic Oncology
Εκδότης:
Lippincott Williams and Wilkins
Λέξεις-κλειδιά:
epidermal growth factor receptor; growth factor receptor bound protein 2; K ras protein; EGFR protein, human; epidermal growth factor receptor; GRB2 protein, human; growth factor receptor bound protein 2; tumor marker, aged; Article; cancer cell line; cancer localization; cancer patient; cancer prognosis; cancer survival; controlled study; female; gene mutation; human; human cell; immunofluorescence; lung adenocarcinoma; male; MCF 7 cell line; priority journal; protein expression; protein phosphorylation; protein protein interaction; adenocarcinoma; adult; biosynthesis; cohort analysis; genetics; lung tumor; MAPK signaling; MCF-7 cell line; metabolism; middle aged; mutation; pathology; prognosis; tumor cell line; very elderly, Adenocarcinoma; Adult; Aged; Aged, 80 and over; Biomarkers, Tumor; Cell Line, Tumor; Cohort Studies; Female; GRB2 Adaptor Protein; Humans; Lung Neoplasms; Male; MAP Kinase Signaling System; MCF-7 Cells; Middle Aged; Mutation; Prognosis; Receptor, Epidermal Growth Factor
DOI:
10.1016/j.jtho.2016.06.025
