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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. EGFR-mutant (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.

Titel:	EGFR-GRB2 Protein Colocalization Is a Prognostic Factor Unrelated to Overall EGFR Expression or EGFR Mutation in Lung Adenocarcinoma.
Autor/in / Beteiligte Person:	Toki, MI ; Carvajal-Hausdorf, DE ; Altan, M ; McLaughlin, J ; Henick, B ; Schalper, KA ; Syrigos, KN ; Rimm, DL
Link:	Full Text Finder (Volltext)
Zeitschrift:	Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer, Jg. 11 (2016-11-01), Heft 11, S. 1901-1911
Veröffentlichung:	2016- : New York, NY : Elsevier ; <i>Original Publication</i>: Hagerstown, MD : Lippincott Williams & Wilkins, c2006-, 2016
Medientyp:	academicJournal
ISSN:	1556-1380 (electronic)
DOI:	10.1016/j.jtho.2016.06.025
Schlagwort:	Adenocarcinoma pathology Adenocarcinoma of Lung Adult Aged Aged, 80 and over Biomarkers, Tumor genetics Biomarkers, Tumor metabolism Cell Line, Tumor Cohort Studies ErbB Receptors biosynthesis Female Humans Lung Neoplasms pathology MAP Kinase Signaling System MCF-7 Cells Male Middle Aged Prognosis Adenocarcinoma genetics Adenocarcinoma metabolism ErbB Receptors genetics ErbB Receptors metabolism GRB2 Adaptor Protein metabolism Lung Neoplasms genetics Lung Neoplasms metabolism Mutation
Sonstiges:	Nachgewiesen in: MEDLINE Sprachen: English Publication Type: Journal Article Language: English [J Thorac Oncol] 2016 Nov; Vol. 11 (11), pp. 1901-1911. <i>Date of Electronic Publication: </i>2016 Jul 20. MeSH Terms: Mutation* ; Adenocarcinoma / genetics ; Adenocarcinoma / metabolism ; ErbB Receptors / genetics ; ErbB Receptors / metabolism ; GRB2 Adaptor Protein / metabolism ; Lung Neoplasms / genetics ; Lung Neoplasms / *metabolism ; Adenocarcinoma / pathology ; Adenocarcinoma of Lung ; Adult ; Aged ; Aged, 80 and over ; Biomarkers, Tumor / genetics ; Biomarkers, Tumor / metabolism ; Cell Line, Tumor ; Cohort Studies ; ErbB Receptors / biosynthesis ; Female ; Humans ; Lung Neoplasms / pathology ; MAP Kinase Signaling System ; MCF-7 Cells ; Male ; Middle Aged ; Prognosis References: Cell. 1992 Aug 7;70(3):431-42. (PMID: 1322798) ; Ann Oncol. 2005 Apr;16(4):538-48. (PMID: 15746148) ; Nat Methods. 2006 Dec;3(12):995-1000. (PMID: 17072308) ; J Clin Oncol. 2009 Jan 10;27(2):271-8. (PMID: 19064983) ; J Clin Oncol. 2006 Mar 1;24(7):1219-20; author reply 1220-1. (PMID: 16505443) ; J Immunol Methods. 1991 Mar 1;137(1):103-12. (PMID: 1849153) ; Lancet Oncol. 2008 Oct;9(10):962-72. (PMID: 18804418) ; J Natl Compr Canc Netw. 2013 Jun 1;11(6):645-53; quiz 653. (PMID: 23744864) ; Sci Signal. 2015 Jan 13;8(359):ra4. (PMID: 25587191) ; Oncogene. 2007 May 14;26(22):3291-310. (PMID: 17496923) ; Am J Pathol. 2012 Oct;181(4):1436-42. (PMID: 22877687) ; N Engl J Med. 2005 Jul 14;353(2):133-44. (PMID: 16014883) ; Trans R Soc Trop Med Hyg. 2003 Mar-Apr;97(2):217-25. (PMID: 14584381) ; Radiother Oncol. 2011 Oct;101(1):152-7. (PMID: 21680035) ; PLoS One. 2013;8(3):e55657. (PMID: 23520446) ; Nat Med. 2002 Nov;8(11):1323-7. (PMID: 12389040) ; JAMA Oncol. 2016 Jan;2(1):46-54. (PMID: 26562159) ; Eur Respir J. 2005 Feb;25(2):329-35. (PMID: 15684299) ; J Clin Oncol. 2004 Aug 15;22(16):3238-47. (PMID: 15310767) ; Nat Rev Cancer. 2007 Mar;7(3):169-81. (PMID: 17318210) ; J Clin Oncol. 2010 Feb 20;28(6):918-27. (PMID: 20100958) ; N Engl J Med. 2004 May 20;350(21):2129-39. (PMID: 15118073) ; J Natl Compr Canc Netw. 2012 Jul 1;10(7):847-56. (PMID: 22773800) ; J Clin Oncol. 2005 Sep 1;23(25):5900-9. (PMID: 16043828) ; Ther Adv Med Oncol. 2009 Nov;1(3):137-44. (PMID: 21789118) ; J Clin Oncol. 2005 Nov 1;23(31):8081-92. (PMID: 16204011) ; Lung Cancer. 2010 Sep;69(3):272-8. (PMID: 20022659) ; Lancet Oncol. 2009 May;10(5):432-3. (PMID: 19410185) ; Eur Respir J. 2002 Oct;20(4):975-81. (PMID: 12412692) ; Lab Invest. 2011 Aug;91(8):1253-61. (PMID: 21519325) ; Nat Rev Cancer. 2010 Nov;10(11):760-74. (PMID: 20966921) ; Mol Cancer Res. 2012 Mar;10(3):428-40. (PMID: 22232519) ; N Engl J Med. 2005 Jul 14;353(2):123-32. (PMID: 16014882) ; J Thorac Oncol. 2013 Jul;8(7):823-59. (PMID: 23552377) ; J Natl Cancer Inst. 2005 Dec 21;97(24):1808-15. (PMID: 16368942) ; Br J Cancer. 2004 Jul 19;91(2):208-12. (PMID: 15187994) ; JAMA. 2014 Apr 9;311(14):1430-7. (PMID: 24715074) ; Lung Cancer. 2014 Jul;85(1):66-73. (PMID: 24780111) ; Lancet Oncol. 2011 Aug;12 (8):795-805. (PMID: 21782507) Grant Information: P30 CA016359 United States CA NCI NIH HHS; P50 CA196530 United States CA NCI NIH HHS; UL1 TR001863 United States TR NCATS NIH HHS Contributed Indexing: Keywords: Adenocarcinoma; EGFR; GRB2; NSCLC; Proximity ligation assay; Quantitative immunofluorescence Substance Nomenclature: 0 (Biomarkers, Tumor) ; 0 (GRB2 Adaptor Protein) ; 0 (GRB2 protein, human) ; EC 2.7.10.1 (EGFR protein, human) ; EC 2.7.10.1 (ErbB Receptors) Entry Date(s): Date Created: 20160725 Date Completed: 20171101 Latest Revision: 20190221 Update Code: 20231215 PubMed Central ID: PMC5075503

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EGFR-GRB2 Protein Colocalization Is a Prognostic Factor Unrelated to Overall EGFR Expression or EGFR Mutation in Lung Adenocarcinoma.