Growth factor receptors as therapeutic targets: strategies to inhibit the insulin-like growth factor I receptor

Oncogene. 2003 Sep 29;22(42):6589-97. doi: 10.1038/sj.onc.1206772.


Neoplastic transformation is often related to abnormal activation of growth factor receptors and their signaling pathways. The concept of targeting specific tumorigenic receptors and/or signaling molecules has been validated by the development and successful clinical application of drugs acting against the epidermal growth factor receptor 2 (HER2/neu, Erb2), the epidermal growth factor receptor 1 (EGFR, HER1), the Brc-Abl kinase, the platelet-derived growth factor receptor, and c-kit. This review will focus on the next promising therapeutic target, the insulin-like growth factor I receptor (IGF-IR). IGF-IR has been implicated in a number of neoplastic diseases, including several common carcinomas. From a pharmaceutical standpoint, of particular importance is that IGF-IR appears to be required for many transforming agents (genetic, viral, chemical) to act, but is not obligatory for the function of normal adult cells. The tumorigenic potential of IGF-IR is mediated through its antiapoptotic and transforming signaling, and in some cases through induction of prometastatic pathways. Preclinical studies demonstrated that downregulation of IGF-IR reversed the neoplastic phenotype and sensitized cells to antitumor treatments. The strategies to block IGF-IR function employed anti-IGF-IR antibodies, small-molecule inhibitors of the IGF-IR tyrosine kinase, antisense oligodeoxynucleotides and antisense RNA, small inhibitory RNA, triple helix, dominant-negative mutants, and various compounds reducing ligand availability. The experience with these strategies combined with the knowledge gained with current anti-growth factor receptor drugs should streamline the development of anti-IGF-IR therapeutics.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.
  • Review

MeSH terms

  • Drug Design
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Neoplasms / genetics*
  • Neoplasms / therapy
  • Oligodeoxyribonucleotides, Antisense / therapeutic use
  • RNA, Antisense / genetics
  • RNA, Small Interfering / genetics
  • Receptor, IGF Type 1 / antagonists & inhibitors*
  • Receptors, Growth Factor / antagonists & inhibitors
  • Receptors, Growth Factor / genetics*
  • Signal Transduction / genetics
  • Signal Transduction / physiology


  • Oligodeoxyribonucleotides, Antisense
  • RNA, Antisense
  • RNA, Small Interfering
  • Receptors, Growth Factor
  • Receptor, IGF Type 1