IGF-1R Overview
IGF-1R activates key signaling pathways

The Insulin-like Growth Factor (IGF) pathway is a fundamental mechanism of cell growth and survival. Activation of this pathway by the binding of the growth factor IGF-1 to the receptor IGF-1R triggers a complex signaling cascade that stimulates cell growth, proliferation, and differentiation, and drives survival.

The IGF Signaling System in Normal Cell Growth
The IGF signaling system

The IGF pathway is a stimulatory signaling system that is integral to the growth of many tissues.^1-3 There are several components to this system, including ligands, receptors, and binding proteins, which together help regulate growth.^1,2

• IGF-1R activation is highly ligand-dependent³
  • Ligands IGF-1 and -2 may be produced by the liver, tumor cells, and/or other tissues to activate IGF-1R¹
  • Growth hormone is the key stimulator of IGF-1 production from the liver¹
  
  
• IGF-1R exists as a homodimer of two IGF-1R subunits or as a heterodimer with an insulin receptor (IR) subunit³
  • IGF-1 stimulates IGF-1R and the IGF-1R/IR heterodimers^1,3
  • Insulin only stimulates the activity of IR and IGF-1R/IR heterodimers^1,3
  
  
• IGF-2R binds IGF-2 but cannot transduce a signal^1,2
  • IGF-2R has no intracellular kinase domain^1,2
  
  
• IR binds IGF-2 or insulin to regulate glucose homeostasis
• There are six IGF binding proteins (IGFBP-1 to -6) that can modify the bioavailability of IGF ligands to regulate signaling^1,3

IGF-1R is part of a fundamental signaling pathway found throughout evolution^1,3

IGF-1R is a receptor with high affinity for IGF-1 and -2 that has been shown to stimulate cell growth, survival, differentiation, and proliferation by mediating activation of complex signaling pathways.^1-3 Among the main downstream pathways involved in IGF-1R signaling, PI3K-Akt-mTOR and Raf-MEK-MAPK are thought to be important.^1-5*

The IGF-1R Signaling Pathway in Cancer
The IGF-1R promotes tumor growth and evasion from apoptosis

Evidence from preclinical and clinical studies suggests that signaling through IGF-1R–mediated pathways regulates multiple processes of cancer initiation, progression, and in some instances, resistance to therapy.^1-3 Tumor cells appear to rely on the IGF-1R signaling pathway as a pro-survival and anti-apoptotic mechanism that¹:

• Facilitates malignant transformation^1-3
• Causes growth and progression of established tumors^1-3
• Enhances tumor invasion and metastasis^1-3
• Contributes to resistance to therapy by providing an escape pathway for tumor cells²

IGF-1R signaling may play a role in multiple tumor types

Signaling through IGF-1R has been implicated in lung cancer.

• Elevated plasma levels of IGF-1 were associated with an increased risk of lung cancer¹
• IGF-1, IGF-2, and IGF-1R are expressed in normal lung cells and overexpressed in lung cancer cells^6,7

IGF-1R signaling has also been implicated in breast cancer, prostate cancer, colorectal cancer, sarcoma, multiple myeloma, and other malignancies.^2,3

IGF-1R Is Being Investigated as a Target in Cancer Research
Antitumor activity is observed with selective inhibition of IGF-1R

Preclinical data from studies of multiple tumor types suggest that the IGF-1R signaling pathway should be investigated as a target in cancer research.^1,2

• Selective IGF-1R inhibition may result in:
  • Apoptosis of tumor cells²
  • Inhibition of tumor formation²
  • Inhibition of tumor metastasis³