the insulin-like growth factor 1 receptor pathway in cancer · the insulin-like growth factor 1...

TheInsulin-like Growth Factor 1 Receptor Pathway in Cancer

IGF2

IGF1

IGF1R

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IGF1

IGF2

IGF1R

AktRas

Tumor

An Overview: The IGF1R Pathway Is Necessary for NormalGrowth and Tumorigenesis and Represents a Potential Targetfor Anticancer Therapy

Tumorigenesis is a highly complex pathological process often resultingfrom aberrant activation or inhibition of key signaling pathways that playessential roles in normal development.1 One such pathway is the insulin-like growth factor 1 receptor (IGF1R) pathway, which controls cellularproliferation, survival, and metabolism through the binding of the ligandsinsulin-like growth factor (IGF) 1 and IGF2 to the IGF1R and the down-stream activation of the PI3K/Akt and Ras/MAPK signal transduction cascades.1-3 A host of studies have determined that the IGF1R pathway isdysregulated in a variety of human cancers, including pancreatic, colorectal,prostate, breast, ovarian, bladder, kidney, and lung, and circulating levelsof IGF1 correlate with increased cancer risk.1-4 Furthermore, increasedIGF1R signaling contributes to the development of resistance to some anti-cancer agents targeting different signaling pathways that participate inmolecular cross talk with the IGF pathway.2,5 As such, the IGF1R pathwayrepresents a potential target for anticancer therapy.

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The IGF1R Pathway Is Activated by the Binding of IGF1 or IGF2

IGF1R signaling is predominantly activated by the binding of two structurally

related ligands, IGF1 and IGF2.1,5 IGF1R 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. IGF1R 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

IGF1R and IR and has no signaling component associated with it.5 The

ligands IGF1, IGF2, and insulin are capable of binding to homodimeric or

hybrid IGF1R and IR with varying affinities; however, the primary ligands

for IGF1R 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

IGF2R

Internalization

Degradation

IR-A

IR-BIR-A/IGF1R IR-B/IGF1RIGF1R

IGF1

Insulin

IGF2

Reference: Chao W, et al. Cytokine Growth Factor Rev. 2008;19:111-120.

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IGF1R Signaling Is Modulated by IGF1 and IGF2, ProducedLocally and From Distant Sites

Regulation of IGF1R signaling occurs through multiple steps both systemically

and locally.8 Though IGF1 and IGF2 are produced in many tissues, one

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

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 IGF1R in a variety of tissues

and also suppresses the production of GH in the pituitary gland as part of a

negative feedback loop.8

IGF1R

IGF1R

GHR

LiverBrain

Pituitary

Gland

1. Growth hormone (GH) producedby the pituitary gland stimulatesIGF production from the liver

2. IGFBPsproduced in the liverbind to IGF

3. In a variety of tissues,IGF dissociates fromIGFBP-3 and binds to IGF1R

4. IGF1R activationresults in adecrease in GHproduction by the pituitarygland

© iStockphoto.com/Jana Blašková GHR = growth hormone receptor.


Activation of IGF1R Triggers Intracellular Signaling Cascades

IGF1 or IGF2 ligands that are not bound by IGFBP are free tobind to the extracellular α-chains of the IGF1R, resulting inhomodimerization of the receptor and autophosphorylation of the intracellular juxtamembrane tyrosine kinase domains attyrosine 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 incell proliferation, survival, and metabolism.2

IGF1IGF2

IRS1Shc

IGF1R


IGF1

IGF2

Binding of

IGF1 or IGF2

Cell Survival and

Metabolism PathwayCell Proliferation

Pathway

Shc

Grb2SOSRaf Ras

MEK

IRS1

PI3K

PIP2

PIP3

IGF1R

Akt

ERK

PTEN

IGF1R Signaling Regulates Cell Survival, Metabolic Activity,and Proliferation Through Activation of PI3K/Akt andRas/MAPK Pathways

Activation of the IGF1R pathway and autophosphorylation of the receptorcreates docking sites for the adaptor proteins IRS1 and Shc.1,8,9 IRS1 activatesthe p85 subunit of PI3K, which in turn phosphorylates membrane-boundPIP2 to create PIP3. PIP3 recruits Akt to the membrane where it becomesactivated to regulate cell metabolism, promote cell cycle progression, andinhibit pro-apoptotic signaling by impinging upon downstream targetsincluding mTOR, GSK3-β, BAD, and FOXO.1,9,10 Shc recruits Grb2 and SOSproteins to activate Ras by stimulating GDP exchange for GTP.8 ActivatedRas triggers the classical MAPK pathway, characterized by the sequentialactivation 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


IGF1R

Overexpression of IGF1R pathwaycomponents in the tumor

High circulating levels of IGF1or IGFBP-3 are associatedwith an increased risk oftumorigenesis

Tumor

Rationale for Targeting IGF1R in Cancer: IGF1R Signaling IsNecessary for Tumorigenesis

Overexpression of IGF1, IGF2, and/or IGF1R may contribute to tumor

progression in humans.1 IGF1R 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 IGF1R pathway compo-

nents 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

Increased IGF1R 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

IGF1R pathway represents a potential target in the treatment of cancer

worth further investigation.2,5


Summary: The IGF1R Pathway in Cancer

The IGF1R pathway plays a central role in cell proliferation, survival (protection

from apoptosis), and the regulation of cellular metabolism.1-3 IGF1R signaling is

necessary for tumorigenesis. Overexpression of IGF1R 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 IGF1R signaling contributes to the

development of resistance to various anticancer agents.2,5,14 Thus, the IGF1R

pathway represents a potential therapeutic target in cancer.1,4,14

IGF1

IGF2

Shc

Grb2SOS

RafRas

MEK

IRS1

PI3K

PIP2

PIP3

IGF1R

Akt

ERK

PTEN

Translation

mTOR


1. Samani AA, et al. Endocr Rev. 2007;28:20-47.2. Tao Y, et al. Nat Clin Pract Oncol. 2007;4:591-602. 3. Pollak M. Nat Rev Cancer. 2008;8:915-928. 4. Yuen JSP, et al. Expert Opin Ther Targets. 2008;12:589-603. 5. Casa AJ, et al. Front Biosci. 2008;13:3273-3287.6. Chao W, et al. Cytokine Growth Factor Rev. 2008;19:111-120.7. Fürstenberger G, et al. Lancet Oncol. 2002;3:298-302.8. Ryan PD, et al. Oncologist. 2008;13:16-24.9. Kooijman R. Cytokine Growth Factor Rev. 2006;17:305-323.

10. Mitsiades CS. Curr Cancer Drug Targets. 2004;4:235-256.11. Pratilas CA, et al. Clin Cancer Res. 2010;16:3329-3334.12. Bergmann U, et al. Cancer Res. 1995;55:2007-2011.13. Martin JL, et al. J Biol Chem. 2009;284:25542-25552.14. Jones HE, et al. Endocr Relat Cancer. 2006;13:S45-S51.15. McCubrey JA, et al. Biochim Biophys Acta. 2007;1773:

1263-1284.

References Notes


Notes

Sleeve


Provided as an educational resource. Do not copy or distribute. ©2012 Amgen Inc. All rights reserved. G64823-R1-V1 64825-R2-V1

Current as of February 2012.

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.


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