A236: Importance of the insulin-like growth factor (IGF) signal transduction pathway and the type I IGF receptor in gastric cancer cells without HER2, FGFR2 or MET amplification
1Northern Institute for Cancer Research, Newcastle upon Tyne, UK,2Newcastle University Institute for Ageing, Department of Pathology, Newcastle upon Tyne, UK,3Northern Oesophago-gastric Cancer Unit, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
Patients with advanced gastric cancer have limited therapeutic options and the response rates are low. Patients with HER-2-positive tumours are eligible for trastuzumab and inhibitors of c-Met and FGFR are in clinical trial for patients with amplified MET and FGFR2, respectively. The aim of the present study was to investigate the importance of the IGF signal transduction pathway in gastric cancer cells that are not driven by these three tyrosine kinase receptors.
Expression of receptors and components of the IGF signal transduction pathway was measured in gastric cancer cells and patient samples by western transfer analysis. The survival effect of IGF-1 on triple-negative gastric cancer cell death induced by prevention of attachment or tyrosine kinase inhibition was tested. The proliferative effect of IGF-1 was investigated. The importance of the type I IGF receptor on proliferation and cell cycle progression was assessed by gene knockdown.
Triple-negative gastric cancer cells expressed variable but in some cases high levels of the type I IGF and insulin receptors and their downstream effector proteins. IGF-1 protected triple-negative gastric cancer cells from cell death and stimulated their growth. The IGF-survival effect was more pronounced in patient samples compared to established cell lines. The IGF-proliferative effect was prevented by knockdown of the type I IGF receptor. The overall importance of the type I IGF receptor was demonstrated after knockdown of the type I IGF receptor by the dramatic growth inhibition of cells cultured in full medium. Further, the proportion of cells in S-phase and mitoticphase of the cell cycle was reduced dramatically in the absence of the type I IGF receptor.
Our data indicate that the IGF signal transduction pathway merits serious consideration as a therapeutic target in gastric cancer patients that are ineligible for anti-HER2, c-Met or FRFR2 targeted therapies.