Novel therapeutic targets in advanced gastric cancer : the insulin-like growth factor signal transduction pathway

Abstract

Patients with advanced gastric cancer have limited therapeutic options to which response rates are low. Very few targeted therapies are available. There is an urgent need for novel targeted inhibitors for patients who are either ineligible for the existing targeted therapies or have developed resistance. Several studies have supported the importance of the IGF signal transduction pathway in cancer cell survival and proliferation and inhibitors of the type I IGF and insulin receptors have reached clinical trials in various cancer types. To date, the role of the IGF signal transduction pathway in gastric cancer has not been investigated thoroughly. The aim of the present study is to investigate the importance of the IGF signal transduction pathway in gastric cancer cells and the effect of inhibition of IGF signal transduction in cell survival and proliferation. IGF-1 was protective against gastric cancer cell death induced by protein kinase inhibition and disruption of cell attachment to the extracellular matrix. The survival effect was mediated by the PI3K/Akt pathway. The survival effect of IGF-1 was even more prominent in ex vivo cultures of gastric cancer cells established from patient ascites. IGF-1 stimulated proliferation of gastric cancer cells, which was mediated by activation of the Ras/Raf/ERK pathway. IGF-2 and insulin induced also gastric cancer cell survival and proliferation. Inhibition of the type I IGF receptor by siRNA knockdown reduced proliferation of gastric cancer cells and ex vivo cultures by inhibition of cell mitosis and DNA synthesis. Inhibition of the insulin receptor by siRNA knockdown resulted in the induction of apoptosis. Combined inhibition of the two receptors with a small molecule tyrosine kinase inhibitor reduced effectively cell growth and induced apoptosis. Our results suggest that inhibition of the type I IGF and insulin receptors could be a valid therapeutic strategy for advanced gastric cancer patients who are not eligible for the currently available targeted treatments.