Small molecule inhibitors of the IGF-1R/IR axis for the treatment of cancer

Abstract

Introduction: The IGF-1 receptor (IGF-1R) is a receptor tyrosine kinase and is well established as a key regulator of tumor cell growth and survival. There is also a growing body of data to support a role for the structurally and functionally related insulin receptor (IR) in human cancer. Bidirectional crosstalk between IGF-1R and IR is observed, where specific inhibition of either receptor confers a compensatory increase in the activity for the reciprocal receptor, therefore dual inhibition of both IGF-1R and IR may be important for optimal efficacy. The importance of IGF-1R and IR as targets in cancer is further underscored by their contribution to resistance against both cytotoxic and molecularly targeted anti-cancer therapeutics. Currently, both IGF-1R-neutralizing antibodies and small-molecule tyrosine kinase inhibitors of IGF-1R/IR are in clinical development.

Areas covered: The importance of IGF-1R and IR as cancer targets and how IGF-1R/IR inhibitors may sensitize tumor cells to the anti-proliferative and pro-apoptotic effects of other anti-tumor agents. The potential advantages of small molecule IGF-1R/IR inhibitors compared with IGF-1R-specific neutralizing antibodies, and the characteristics of small-molecule IGF-1R inhibitors that have entered clinical development.

Expert opinion: Because of compensatory crosstalk between IGF-1R and IR, dual IGF-1R and IR tyrosine kinase inhibitors may have superior anti-tumor activity compared to anti-IGF-1R specific antibodies. The clinical success for IGF-1R/IR inhibitors may ultimately be dependent upon our ability to correctly administer these agents to the right niche patient subpopulation using single agent therapy, when appropriate, or using the right combination therapy.