Targeting the insulin-like growth factor receptor pathway in lung cancer: problems and pitfalls

The insulin-like growth factor (IGF) pathway is a complex pathway involving interactions between membrane-bound receptors, ligands, binding proteins, downstream effectors, and other receptor tyrosine kinase signaling cascades. The IGF pathway has been identified as a potential therapeutic target in non-small cell lung cancer (NSCLC) based on the following provocative factors. Preclinical observations in NSCLC have shown that this pathway is involved in tumor cell proliferation, survival, and invasiveness. In addition, IGF-1R protein expression is found in a significant number of non-small cell tumor specimens. Initial therapeutic efforts involved the development of monoclonal antibodies and tyrosine kinase inhibitors that target IGF-1R, a transmembrane receptor tyrosine kinase. Enthusiasm for targeting this pathway increased when a randomized phase II study showed that combining an anti-IGF-1R monoclonal antibody (figitumumab) with a platinum doublet resulted in a higher response rate and trends for superior progression-free survival and overall survival. Subsequently, a phase III study failed to confirm the promising results observed in the phase II trial. Currently, investigators are studying different monoclonal antibodies and tyrosine kinases targeting IGF-1R. In unselected patients, results presented thus far do not suggest efficacy of this agent. However, retrospective subgroup analyses suggest that circulating IGF-1 levels might identify patients who could benefit from treatment with an IGF-1R monoclonal antibody and may warrant further exploratory studies for predictive molecular markers. The purpose of this paper is to briefly discuss the IGF pathway and its relationship with other signaling pathways in lung cancer and to review the ongoing IGF clinical trials and efforts to identify predictive molecular markers.