The Insulin-like Growth Factor 1 Receptor Pathway in Cancer

Transcription

1 IGF2 IGF1 The Insulin-like Growth Factor 1 Receptor Pathway in Cancer

2 An Overview: The Pathway Is Necessary for Normal Growth and Tumorigenesis and Represents a Potential Target for Anticancer Therapy IGF1 Tumorigenesis is a highly complex pathological process often resulting from aberrant activation or inhibition of key signaling pathways that play essential roles in normal development. 1 One such pathway is the insulinlike growth factor 1 receptor () pathway, which controls cellular proliferation, survival, and metabolism through the binding of the ligands insulin-like growth factor (IGF) 1 and IGF2 to the and the downstream activation of the PI3K/Akt and Ras/MAPK signal transduction cascades. 1-3 A host of studies have determined that the pathway is dysregulated in a variety of human cancers, including pancreatic, colorectal, prostate, breast, ovarian, bladder, kidney, and lung, and circulating levels of IGF1 correlate with increased cancer risk. 1-4 Furthermore, increased signaling contributes to the development of resistance to some anticancer agents targeting different signaling pathways that participate in molecular cross talk with the IGF pathway. 2,5 As such, the pathway represents a potential target for anticancer therapy. Ras IGF2 Akt Tumor

3 IGF1 IGF2 The Pathway Is Activated by the Binding of IGF1 or IGF2 Insulin signaling is predominantly activated by the binding of two structurally related ligands, IGF1 and IGF2. 1,5 is a transmembrane receptor tyrosine kinase (RTK) consisting of two extracellular α-chains and two intracellular β-chains linked by disulfide bonds to form a tetramer. shares 60% amino acid sequence homology with the insulin receptor (IR) and each can form homodimers or hybrid heterodimers with the other. 1,5 Another receptor in this family, IGF2R, is structurally and functionally distinct from IR-B IR-A/ IR-B/ IGF2R and IR and has no signaling component associated with it. 5 The ligands IGF1, IGF2, and insulin are capable of binding to homodimeric or IR-A hybrid and IR with varying affinities; however, the primary ligands for are IGF1 and IGF2. 1,5,6 IGF1 and IGF2 share 62% homology in amino acid sequence and 40% homology to pro-insulin. 1,5,7 IGF1 and IGF2 are produced by multiple tissues, especially the liver, and circulate in the blood where they exert endocrine as well as autocrine and paracrine effects. 7 Internalization Degradation Reference: Chao W, et al. Cytokine Growth Factor Rev. 2008;19:

4 Signaling Is Modulated by IGF1 and IGF2, Produced Locally and From Distant Sites 1. Growth hormone (GH) produced by the pituitary gland stimulates IGF production from the liver Regulation of signaling occurs through multiple steps both systemically and locally. 8 Though IGF1 and IGF2 are produced in many tissues, one GHR predominant site of IGF production is the liver, where they are secreted in response to growth hormone (GH). 8 After IGFs are secreted, less than 1% circulate in a free, unbound state; the majority are bound to one of six related Brain Liver high-affinity IGF binding proteins (IGFBPs). 1,7,8 Greater than 90% of circulating IGFs are bound specifically to IGFBP-3. 7 Through binding to IGFs, IGFBPs control IGF half-life as well as their availability to bind to receptors. 8 Dissociation of IGFs from IGFBPs allows the ligands to bind to in a variety of tissues and also suppresses the production of GH in the pituitary gland as part of a 4. activation results in a decrease in GH production by the pituitary gland Pituitary Gland 2. IGFBPs produced in the liver bind to IGF negative feedback loop In a variety of tissues, IGF dissociates from IGFBP-3 and binds to istockphoto.com/jana Blašková GHR = growth hormone receptor.

5 Activation of Triggers Intracellular Signaling Cascades IGF1 or IGF2 ligands that are not bound by IGFBP are free to bind to the extracellular α-chains of the, resulting in homodimerization of the receptor and autophosphorylation of the intracellular juxtamembrane tyrosine kinase domains at tyrosine 950, creating docking sites for adaptor proteins such as IRS1 and Shc. 1 Phosphorylation and binding of adaptor proteins initiates downstream signaling events that result in cell proliferation, survival, and metabolism. 2 IGF1 IGF2 Shc IRS1

6 Signaling Regulates Cell Survival, Metabolic Activity, and Proliferation Through Activation of PI3K/Akt and Ras/MAPK Pathways IGF1 IGF2 Binding of IGF1 or IGF2 Activation of the pathway and autophosphorylation of the receptor creates docking sites for the adaptor proteins IRS1 and Shc. 1,8,9 IRS1 activates the p85 subunit of PI3K, which in turn phosphorylates membrane-bound PIP 2 to create PIP 3. PIP 3 recruits Akt to the membrane where it becomes activated to regulate cell metabolism, promote cell cycle progression, and inhibit pro-apoptotic signaling by impinging upon downstream targets including mtor, GSK3-β, BAD, and FOXO. 1,9,10 Shc recruits Grb2 and SOS proteins to activate Ras by stimulating GDP exchange for GTP. 8 Activated Ras triggers the classical MAPK pathway, characterized by the sequential activation of the kinases Raf, MEK, and ERK. ERK activation leads to transcription of target genes necessary for cell proliferation, such as cyclin D and Myc. 8,11 Cell Proliferation Pathway Raf Ras MEK SOS Grb2 Shc IRS1 PI3K PIP 2 Cell Survival and Metabolism Pathway PTEN PIP3 Akt ERK

7 Rationale for Targeting in Cancer: Signaling Is Necessary for Tumorigenesis Overexpression of IGF1, IGF2, and/or may contribute to tumor progression in humans. 1 has been shown to be overexpressed in a number of human cancers including pancreatic, colorectal, prostate, breast, ovarian, bladder, and lung. 2 IGF1 and IGF2 have also been found to be expressed at higher than normal levels in cancerous tissues and cell lines. 1,6,12 IGF1 mrna levels were higher in human cancerous pancreatic tissue and cell lines compared to normal. 12 There is even evidence for a correlation of increased levels of the binding protein IGFBP-3 (in tumor tissue or in circulation) with increased tumor growth in some types of cancers, including breast, prostate, pancreatic, renal cell, and non-small cell lung cancers. 8,13 Furthermore, high levels of pathway components may be predictive of cancer risk. 2 Experimental and clinical studies have found that elevated plasma concentrations of IGF1 correlates with increased risk of developing breast, colorectal, prostate, and lung cancers. 2 High circulating levels of IGF1 or IGFBP-3 are associated with an increased risk of tumorigenesis Increased signaling contributes to the development of resistance to some anticancer agents targeting different signaling pathways that participate in molecular crosstalk with the IGF pathway. 2,5,14 Thus, the pathway represents a potential target in the treatment of cancer worth further investigation. 2,5 Tumor Overexpression of pathway components in the tumor

8 IGF2 Summary: The Pathway in Cancer The pathway plays a central role in cell proliferation, survival (protection from apoptosis), and the regulation of cellular metabolism. 1-3 signaling is IGF1 necessary for tumorigenesis. Overexpression of pathway components is described in a number of human cancers, such as pancreatic, colorectal, prostate, breast, ovarian, bladder, kidney, and lung. 1,4 Downstream PI3K/Akt and Ras/MAPK signaling cascades are commonly activated in human cancers by aberrant growth factor signaling and genetic mutation. 10,15 signaling contributes to the development of resistance to various anticancer agents. 2,5,14 Thus, the PIP 2 pathway represents a potential therapeutic target in cancer. 1,4,14 Raf Ras SOS Grb2 Shc IRS1 PI3K PIP3 Akt MEK PTEN ERK mtor Translation

9 References 1. Samani AA, et al. Endocr Rev. 2007;28: Tao Y, et al. Nat Clin Pract Oncol. 2007;4: Pollak M. Nat Rev Cancer. 2008;8: Yuen JSP, et al. Expert Opin Ther Targets. 2008;12: Casa AJ, et al. Front Biosci. 2008;13: Chao W, et al. Cytokine Growth Factor Rev. 2008;19: Fürstenberger G, et al. Lancet Oncol. 2002;3: Ryan PD, et al. Oncologist. 2008;13: Kooijman R. Cytokine Growth Factor Rev. 2006;17: Mitsiades CS. Curr Cancer Drug Targets. 2004;4: Pratilas CA, et al. Clin Cancer Res. 2010;16: Bergmann U, et al. Cancer Res. 1995;55: Martin JL, et al. J Biol Chem. 2009;284: Jones HE, et al. Endocr Relat Cancer. 2006;13:S45-S McCubrey JA, et al. Biochim Biophys Acta. 2007;1773: Notes

10 Notes Sleeve

11 Current as of February Statements in this booklet are based on the company s current beliefs and Amgen disclaims any duty to update. For more information about Amgen and its business, including risks and uncertainties, please refer to Amgen s filings with the US Securities & Exchange Commission. Provided as an educational resource. Do not copy or distribute Amgen Inc. All rights reserved. G64823-R1-V R2-V1