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)

EBioMedicine. 2019 Jan:39:207-214. doi: 10.1016/j.ebiom.2018.11.036. Epub 2018 Nov 22.

Abstract

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: 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: 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: 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).

Keywords: EGFR mutations; Integrin-linked kinase; NSCLC; Signaling pathways; Src homology 2 domain-containing phosphatase 2.

MeSH terms

  • Aged
  • Carcinoma, Non-Small-Cell Lung / drug therapy
  • Carcinoma, Non-Small-Cell Lung / genetics*
  • 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 Kinase Inhibitors / therapeutic use
  • Protein Serine-Threonine Kinases / genetics*
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11 / genetics*
  • Regression Analysis
  • Up-Regulation*

Substances

  • HGF protein, human
  • IL6 protein, human
  • Interleukin-6
  • Protein Kinase Inhibitors
  • Hepatocyte Growth Factor
  • integrin-linked kinase
  • EGFR protein, human
  • ErbB Receptors
  • Protein Serine-Threonine Kinases
  • PTPN11 protein, human
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11