The type I insulin-like growth factor receptor pathway: a key player in cancer therapeutic resistance

Abstract

The insulin-like growth factor (IGF) ligands stimulate cellular proliferation and survival by activating the type I insulin-like growth factor receptor (IGF-IR). As a result, the IGF signaling system is implicated in a number of cancers, including those of the breast, prostate, and lung. In addition to mitogenic and anti-apoptotic roles that may directly influence tumor development, IGF-IR also appears to be a critical determinant of response to numerous cancer therapies. This review describes the role of the IGF-IR pathway in mediating resistance to both general cytotoxic therapies, such as radiation and chemotherapy, and targeted therapies, such as tamoxifen and trastuzumab. It concludes with a description of approaches to target IGF-IR and argues that inhibition of IGF signaling, in conjunction with standard therapies, may enhance the response of cancer cells to multiple modalities.

Cancer cells promote survival through depletion of the von Hippel–Lindau tumor suppressor by protein crosslinking

“…IGF-1R is a key mediator of tumor cell survival and is overexpressed in many cancers (Casa et al, 2008;Yuen et al, 2009). IGF-1R is downregulated by VHL in an HIF-1a-independent manner (Yuen et al, 2009).…”

Superior Antitumor Activity of a Novel Bispecific Antibody Cotargeting Human Epidermal Growth Factor Receptor 2 and Type I Insulin-like Growth Factor Receptor

“…Various mechanisms may account for this resistance, which likely involve the PI3K/Akt pathway, including elevated HER2-associated receptors and other receptors (28,29), cross activation between HER2 and other receptors (30)(31)(32), blockage of trastuzumab by membrane-associated glycoproteins such as mucin-4, removal of the trastuzumab epitope by cleavage or loss of HER2 expression, and increased HER2 expression. Accumulating evidence shows that cross-talk between HER2 and IGF-IR, including receptor heterodimerization and transactivation, and elevated IGF-IR signaling are associated with trastuzumab resistance (31,(33)(34)(35). Overexpression of IGF-IR in HER2-overexpressing breast cancer cell lines results in trastuzumab resistance in vitro (36).…”

Efficacy of and resistance to anti-IGF-1R therapies in Ewing's sarcoma is dependent on insulin receptor signaling

“…Insulin-like growth factor (IGF) signaling has been implicated as a critical contributor to malignant transformation and tumor resistance to cytotoxic chemotherapy, targeted therapies, hormonal therapy and radiation (for reviews see Casa et al, 2008;Chitnis et al, 2008). As a result, IGF signaling has become an attractive target for development of novel anticancer agents, and a large number of compounds, including blocking antibodies and tyrosine kinase inhibitors (TKIs) disrupting IGF-I receptor (IGF-1R) functions are in preclinical and clinical development.…”