Insulin/Insulin-like growth factors in cancer: new roles for the aryl hydrocarbon receptor, tumor resistance mechanisms, and new blocking strategies

Abstract

The insulin-like growth factor 1 receptor (IGF1R) and the insulin receptor (IR) are receptor tyrosine kinases that are expressed in cancer cells. The results of different studies indicate that tumor proliferation and survival is dependent on the IGF1R and IR, and that their inhibition leads to reductions in proliferation and increases in cell death. Molecular targeting therapies that have been used in solid tumors include anti-IGF1R antibodies, anti-IGF1/IGF2 antibodies, and small molecule inhibitors that suppress IGF1R and IR kinase activity. New advances in the molecular basis of anti-IGF1R blocking antibodies reveal they are biased agonists and promote the binding of IGF1 to integrin β3 receptors in some cancer cells. Our recent reports indicate that pharmacological aryl hydrocarbon receptor (AHR) ligands inhibit breast cancer cell responses to IGFs, suggesting that targeting AHR may have benefit in cancers whose proliferation and survival are dependent on insulin/IGF signaling. Novel aspects of IGF1R/IR in cancer, such as biased agonism, integrin β3 signaling, AHR, and new therapeutic targeting strategies will be discussed.

Keywords: AHR; IGF1; IGF1R; MED-573; OSI-906; biased-agonism; insulin; insulin receptor-A subtype.

Figure 1

Figitumumab (CP) is a biased agonist of the IGF1R that selectively promotes β-arrestin1 (β-arr1) signaling in cancer cells. (A) IGF1 binding to and activation of the IGF1R stimulates the β-arr1 pathway that leads to proteasomal degradation of the IGF1R through a ubiquitin (Ub)-mediated mechanism and ERK activation. IGF1 binding to the IGF1R also induces IGF1R autophosphorylation and this serves to increase the kinase pathway that promotes the phosphorylation and activation of AKT. (B) CP binding to the IGF1R preferentially increases β-arr1 signaling, and inhibits the IGF1R kinase pathway. By this mechanism, CP downregulates IGF1R and AKT signaling, and increases ERK-mediated mitogenic signaling.

Figure 2

Mechanism of action of MEDI-573, anti-IGF1R antibodies, and OSI-906 in cancer cells and tumor angiogenesis. IGF2 binding to insulin receptor subtype A (IR-A) and IGF1 binding to IGF1R in cancer cells and tumor blood vessels promotes cancer cell survival and proliferation as well as tumor angiogenesis. MEDI-573 is a human antibody that neutralizes IGF2 and IGF1 and thus inhibits the cancer effects of both IGF ligands. Anti-IGF1R antibodies inhibit IGF1 signaling through IGF1R, but not IGF2 signaling mediated by IR-A. OSI-906 is a small molecule inhibitor that inhibits IGF1R and IR autophosphorylation and therefore IGF1 and IGF2 cancer effects.