Integrin-linked kinase (ILK) and src homology 2 domain-containing phosphatase 2 (SHP2): Novel targets in EGFR-mutation positive non-small cell lung cancer (NSCLC).
Aged
Carcinoma, Non-Small-Cell Lung
/ drug therapy
ErbB Receptors
/ genetics
Female
Gene Expression Regulation, Neoplastic
Hepatocyte Growth Factor
/ genetics
Humans
Interleukin-6
/ genetics
Lung Neoplasms
/ genetics
MAP Kinase Signaling System
Male
Mutation
Progression-Free Survival
Protein Kinase Inhibitors
/ pharmacology
Protein Serine-Threonine Kinases
/ genetics
Protein Tyrosine Phosphatase, Non-Receptor Type 11
/ genetics
Regression Analysis
Up-Regulation
EGFR mutations
Integrin-linked kinase
NSCLC
Signaling pathways
Src homology 2 domain-containing phosphatase 2
Journal
EBioMedicine
ISSN: 2352-3964
Titre abrégé: EBioMedicine
Pays: Netherlands
ID NLM: 101647039
Informations de publication
Date de publication:
Jan 2019
Jan 2019
Historique:
received:
05
11
2018
revised:
16
11
2018
accepted:
16
11
2018
pubmed:
27
11
2018
medline:
14
6
2019
entrez:
27
11
2018
Statut:
ppublish
Résumé
The activation of multiple signaling pathways jeopardizes the clinical efficacy of EGFR tyrosine kinase inhibitors (TKIs) in EGFR-mutation positive non-small cell lung cancer (NSCLC). Integrin-linked kinase (ILK) regulates the interactions between tumor cells and extracellular environment to activate signaling pathways and promote cell proliferation, migration, and epithelial-mesenchymal transition. Src homology 2 domain-containing phosphatase 2 (SHP2) is essential for receptor tyrosine kinase signaling and mitogen-activated protein kinase (MAPK) pathway activation. We analyzed tumor ILK, β-receptor subunit glycoprotein 130 (gp130), SHP2, and stromal hepatocyte growth factor (HGF) and interleukin-6 (IL-6) mRNA expression in baseline tumor specimens of advanced EGFR-mutation positive NSCLC patients treated with EGFR TKIs. ILK, when highly expressed, was an independent poor prognostic factor for the progression-free survival of the patients, both in the univariate (hazard ratio [HR for disease progression, 2.49; 95% CI, 1.37-4.52; P = .0020]) and in the multivariate (HR 3.74; 95% CI, 1.33-10.56; P = .0126) Cox regression model. Patients with high SHP2 expression had an almost 13-month shorter progression-free survival (P = .0094) and an 18-month shorter overall survival (P = .0182) in comparison to those with low SHP2 mRNA expression. The levels of ILK and SHP2 could be predictive for upfront combinatory therapy of EGFR TKIs plus SHP2 or ILK inhibitors. FUND: A grant from La Caixa Foundation, an Instituto de Salud Carlos III grant (RESPONSE, PIE16/00011), an Instituto de Salud Carlos III grant (PI14/01678), a Marie Skłodowska-Curie Innovative Training Networks European Grant (ELBA No 765492) and a Spanish Association Against Cancer (AECC) grant (PROYE18012ROSE).
Sections du résumé
BACKGROUND
BACKGROUND
The activation of multiple signaling pathways jeopardizes the clinical efficacy of EGFR tyrosine kinase inhibitors (TKIs) in EGFR-mutation positive non-small cell lung cancer (NSCLC). Integrin-linked kinase (ILK) regulates the interactions between tumor cells and extracellular environment to activate signaling pathways and promote cell proliferation, migration, and epithelial-mesenchymal transition. Src homology 2 domain-containing phosphatase 2 (SHP2) is essential for receptor tyrosine kinase signaling and mitogen-activated protein kinase (MAPK) pathway activation.
METHODS
METHODS
We analyzed tumor ILK, β-receptor subunit glycoprotein 130 (gp130), SHP2, and stromal hepatocyte growth factor (HGF) and interleukin-6 (IL-6) mRNA expression in baseline tumor specimens of advanced EGFR-mutation positive NSCLC patients treated with EGFR TKIs.
RESULTS
RESULTS
ILK, when highly expressed, was an independent poor prognostic factor for the progression-free survival of the patients, both in the univariate (hazard ratio [HR for disease progression, 2.49; 95% CI, 1.37-4.52; P = .0020]) and in the multivariate (HR 3.74; 95% CI, 1.33-10.56; P = .0126) Cox regression model. Patients with high SHP2 expression had an almost 13-month shorter progression-free survival (P = .0094) and an 18-month shorter overall survival (P = .0182) in comparison to those with low SHP2 mRNA expression.
INTERPRETATION
CONCLUSIONS
The levels of ILK and SHP2 could be predictive for upfront combinatory therapy of EGFR TKIs plus SHP2 or ILK inhibitors. FUND: A grant from La Caixa Foundation, an Instituto de Salud Carlos III grant (RESPONSE, PIE16/00011), an Instituto de Salud Carlos III grant (PI14/01678), a Marie Skłodowska-Curie Innovative Training Networks European Grant (ELBA No 765492) and a Spanish Association Against Cancer (AECC) grant (PROYE18012ROSE).
Identifiants
pubmed: 30473379
pii: S2352-3964(18)30541-3
doi: 10.1016/j.ebiom.2018.11.036
pmc: PMC6354556
pii:
doi:
Substances chimiques
HGF protein, human
0
IL6 protein, human
0
Interleukin-6
0
Protein Kinase Inhibitors
0
Hepatocyte Growth Factor
67256-21-7
integrin-linked kinase
EC 2.7.1.-
EGFR protein, human
EC 2.7.10.1
ErbB Receptors
EC 2.7.10.1
Protein Serine-Threonine Kinases
EC 2.7.11.1
PTPN11 protein, human
EC 3.1.3.48
Protein Tyrosine Phosphatase, Non-Receptor Type 11
EC 3.1.3.48
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
207-214Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.
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