Insulin receptor functionally enhances multistage tumor progression and conveys intrinsic resistance to IGF-1R targeted therapy

The type 1 insulin-like growth factor receptor (IGF-1R) tyrosine kinase is an important mediator of the protumorigenic effects of IGF-I/II, and inhibitors of IGF-1R signaling are currently being tested in clinical cancer trials aiming to assess the utility of this receptor as a therapeutic target. Despite mounting evidence that the highly homologous insulin receptor (IR) can also convey protumorigenic signals, its direct role in cancer progression has not been genetically defined in vivo, and it remains unclear whether such a role for IR signaling could compromise the efficacy of selective IGF-1R targeting strategies. A transgenic mouse model of pancreatic neuroendocrine carcinogenesis engages the IGF signaling pathway, as revealed by its dependence on IGF-II and by accelerated malignant progression upon IGF-1R overexpression. Surprisingly, preclinical trials with an inhibitory monoclonal antibody to IGF-1R did not significantly impact tumor growth, prompting us to investigate the involvement of IR. The levels of IR were found to be significantly up-regulated during multistep progression from hyperplastic lesions to islet tumors. Its functional involvement was revealed by genetic disruption of the IR gene in the oncogene-expressing pancreatic β cells, which resulted in reduced tumor burden accompanied by increased apoptosis. Notably, the IR knockout tumors now exhibited sensitivity to anti–IGF-1R therapy; similarly, high IR to IGF-1R ratios demonstrably conveyed resistance to IGF-1R inhibition in human breast cancer cells. The results predict that elevated IR signaling before and after treatment will respectively manifest intrinsic and adaptive resistance to anti–IGF-1R therapies.

[1]  D. Yee,et al.  The IGF system and breast cancer. , 2001, Endocrine-related cancer.

[2]  E. Englesberg,et al.  The insulin receptor as a transmitter of a mitogenic signal in Chinese hamster ovary CHO-K1 cells. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[3]  Yang Feng,et al.  Novel human monoclonal antibodies to insulin-like growth factor (IGF)-II that potently inhibit the IGF receptor type I signal transduction function , 2006, Molecular Cancer Therapeutics.

[4]  R. Jirtle.  IGF2 loss of imprinting: a potential heritable risk factor for colorectal cancer. , 2004, Gastroenterology.

[5]  R. Guzman,et al.  Hormones and mammary carcinogenesis in mice, rats, and humans: a unifying hypothesis. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[6]  D. Hanahan,et al.  A second signal supplied by insulin-like growth factor II in oncogene-induced tumorigenesis , 1994, Nature.

[7]  D. Hanahan,et al.  Insulin-like growth factor II is focally up-regulated and functionally involved as a second signal for oncogene-induced tumorigenesis. , 1994, Cold Spring Harbor symposia on quantitative biology.

[8]  D. Hanahan,et al.  Elevated levels of IGF-1 receptor convey invasive and metastatic capability in a mouse model of pancreatic islet tumorigenesis. , 2002, Cancer cell.

[9]  Mieke Schutte,et al.  Phosphatidylinositol-3-OH Kinase or RAS Pathway Mutations in Human Breast Cancer Cell Lines , 2007, Molecular Cancer Research.

[10]  C. Conover,et al.  Functional insulin receptors on human epithelial ovarian carcinoma cells: implications for IGF-II mitogenic signaling. , 2002, Endocrinology.

[11]  A. Belfiore,et al.  Insulin/Insulin-like Growth Factor I Hybrid Receptors Have Different Biological Characteristics Depending on the Insulin Receptor Isoform Involved* , 2002, The Journal of Biological Chemistry.

[12]  W. Bremner,et al.  Advances in male contraception. , 2008, Endocrine reviews.

[13]  A. Costantino,et al.  Insulin receptor activation by IGF-II in breast cancers: evidence for a new autocrine/paracrine mechanism , 1999, Oncogene.

[14]  Peter Bohlen,et al.  A fully human monoclonal antibody to the insulin-like growth factor I receptor blocks ligand-dependent signaling and inhibits human tumor growth in vivo. , 2003, Cancer research.

[15]  Ryan D. Morin,et al.  Mutational evolution in a lobular breast tumour profiled at single nucleotide resolution , 2009, Nature.

[16]  Sandra,et al.  A dominant negative mutant of the insulin-like growth factor-I receptor inhibits the adhesion, invasion, and metastasis of breast cancer. , 1998, Cancer research.

[17]  C. Osborne,et al.  Hormone responsive human breast cancer in long-term tissue culture: effect of insulin. , 1976, Proceedings of the National Academy of Sciences of the United States of America.

[18]  M. Stampfer,et al.  Insulin receptor expression and function in human breast cancer cell lines. , 1992, Cancer research.

[19]  S. Avnet,et al.  Insulin receptor isoform A and insulin-like growth factor II as additional treatment targets in human osteosarcoma. , 2009, Cancer research.

[20]  G. Cavet,et al.  Molecular predictors of response to a humanized anti–insulin-like growth factor-I receptor monoclonal antibody in breast and colorectal cancer , 2009, Molecular Cancer Therapeutics.

[21]  D. Leroith,et al.  Insulin-mediated acceleration of breast cancer development and progression in a nonobese model of type 2 diabetes. , 2010, Cancer research.

[22]  Domenico Coppola,et al.  Expression and distribution of insulin-like growth factor-1 receptor in human carcinomas. , 2003, Human pathology.

[23]  A. Benoliel,et al.  Insulin stimulates haptotactic migration of human epidermal keratinocytes through activation of NF-kappa B transcription factor. , 1997, Journal of cell science.

[24]  S. Hankinson,et al.  Insulin-like growth factors and neoplasia , 2004, Nature Reviews Cancer.

[25]  D. Hanahan,et al.  Differential Contribution to Neuroendocrine Tumorigenesis of Parallel Egfr Signaling in Cancer Cells and Pericytes , 2010, Genes & cancer.

[26]  C. Venot,et al.  Insulin-Like Growth Factor-1 Receptor Inhibition Induces a Resistance Mechanism via the Epidermal Growth Factor Receptor/HER3/AKT Signaling Pathway: Rational Basis for Cotargeting Insulin-Like Growth Factor-1 Receptor and Epidermal Growth Factor Receptor in Hepatocellular Carcinoma , 2009, Clinical Cancer Research.

[27]  Robert H. Bell,et al.  Insulin receptor expression by human prostate cancers , 2009, The Prostate.

[28]  F. Peruzzi,et al.  The IGF‐1 receptor in cancer biology , 2003, International journal of cancer.

[29]  C. Christoffersen,et al.  Mitogenic properties of insulin and insulin analogues mediated by the insulin receptor , 1997, Diabetologia.

[30]  Oriol Casanovas,et al.  Drug resistance by evasion of antiangiogenic targeting of VEGF signaling in late-stage pancreatic islet tumors. , 2005, Cancer cell.

[31]  A novel autocrine loop involving IGF-II and the insulin receptor isoform-A stimulates growth of thyroid cancer. , 2002, The Journal of clinical endocrinology and metabolism.

[32]  P. Brodt,et al.  The receptor for the type I insulin-like growth factor and its ligands regulate multiple cellular functions that impact on metastasis. , 2001, Surgical oncology clinics of North America.

[33]  P. Pisani.  Hyper-insulinaemia and cancer, meta-analyses of epidemiological studies. , 2008, Archives of physiology and biochemistry.

[34]  Masahiro Inoue,et al.  Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis. , 2009, Cancer cell.

[35]  G. Colditz,et al.  Obesity and Cancer , 2010, The oncologist.

[36]  D. Hanahan,et al.  Effects of angiogenesis inhibitors on multistage carcinogenesis in mice. , 1999, Science.

[37]  D. Yee,et al.  Inhibition of Cancer Cell Proliferation and Metastasis by Insulin Receptor Downregulation , 2010, Oncogene.

[38]  A. Feinberg,et al.  Loss of IGF2 Imprinting: A Potential Marker of Colorectal Cancer Risk , 2003, Science.

[39]  S. Andò,et al.  Differential insulin-like growth factor I receptor signaling and function in estrogen receptor (ER)-positive MCF-7 and ER-negative MDA-MB-231 breast cancer cells. , 2001, Cancer research.

[40]  A. Costantino,et al.  Insulin Receptor Isoform A, a Newly Recognized, High-Affinity Insulin-Like Growth Factor II Receptor in Fetal and Cancer Cells , 1999, Molecular and Cellular Biology.

[41]  M. Magnuson,et al.  Analysis of the Cre‐mediated recombination driven by rat insulin promoter in embryonic and adult mouse pancreas , 2000, Genesis.

[42]  A. Belfiore.  The role of insulin receptor isoforms and hybrid insulin/IGF-I receptors in human cancer. , 2007, Current pharmaceutical design.

[43]  R H Hruban,et al.  Gene expression profiles in normal and cancer cells. , 1997, Science.

[44]  A. B. Hassan,et al.  Functional evaluation of novel soluble insulin-like growth factor (IGF)-II–specific ligand traps based on modified domain 11 of the human IGF2 receptor , 2007, Molecular Cancer Therapeutics.

[45]  David A. Tuveson,et al.  The Use of Targeted Mouse Models for Preclinical Testing of Novel Cancer Therapeutics , 2006, Clinical Cancer Research.

[46]  D. Gutmann,et al.  Harnessing preclinical mouse models to inform human clinical cancer trials. , 2006, The Journal of clinical investigation.

[47]  M. Pollak,et al.  Insulin and insulin-like growth factor signalling in neoplasia , 2008, Nature Reviews Cancer.

[48]  C. Kahn,et al.  A muscle-specific insulin receptor knockout exhibits features of the metabolic syndrome of NIDDM without altering glucose tolerance. , 1998, Molecular cell.

[49]  C Collins,et al.  Insulin‐like growth factor I receptor primary structure: comparison with insulin receptor suggests structural determinants that define functional specificity. , 1986, The EMBO journal.

[50]  C. Kahn,et al.  Tissue-Specific Knockout of the Insulin Receptor in Pancreatic β Cells Creates an Insulin Secretory Defect Similar to that in Type 2 Diabetes , 1999, Cell.

[51]  M. Pollak.  Insulin, insulin-like growth factors, insulin resistance, and neoplasia. , 2007 .

[52]  S. Xuan,et al.  Igf1r as a therapeutic target in a mouse model of basal-like breast cancer , 2009, Proceedings of the National Academy of Sciences.

[53]  E. Giovannucci.  Metabolic syndrome, hyperinsulinemia, and colon cancer: a review. , 2007, The American journal of clinical nutrition.

[54]  A. Gualberto,et al.  Emerging role of insulin-like growth factor receptor inhibitors in oncology: early clinical trial results and future directions , 2009, Oncogene.

[55]  D. Hanahan,et al.  Heritable formation of pancreatic beta-cell tumours in transgenic mice expressing recombinant insulin/simian virus 40 oncogenes. , 1985, Nature.

[56]  F. Grantham,et al.  Role of hormones in the growth and regression of human breast cancer cells (MCF-7) transplanted into athymic nude mice. , 1981, Journal of the National Cancer Institute.

[57]  N. Legros,et al.  Influence of insulin deprivation on growth of the 7,12-dimethylbenz(a)anthracene-induced mammary carcinoma in rats subjected to alloxan diabetes and food restriction. , 1972, Cancer research.

[58]  F. Frasca,et al.  The role of insulin receptors and IGF-I receptors in cancer and other diseases. , 2008, Archives of physiology and biochemistry.

[59]  A. Belfiore,et al.  IGF and Insulin Receptor Signaling in Breast Cancer , 2008, Journal of Mammary Gland Biology and Neoplasia.

[60]  D. Yee,et al.  Down-regulation of type I insulin-like growth factor receptor increases sensitivity of breast cancer cells to insulin. , 2007, Cancer research.

[61]  M. Pollack.  Insulin, insulin-like growth factors, insulin resistance, and neoplasia. , 2007, The American journal of clinical nutrition.

[62]  J. Riedemann,et al.  IGF1R signalling and its inhibition. , 2006, Endocrine-related cancer.

[63]  M. Magnuson,et al.  Dual Roles for Glucokinase in Glucose Homeostasis as Determined by Liver and Pancreatic β Cell-specific Gene Knock-outs Using Cre Recombinase* , 1999, The Journal of Biological Chemistry.

[64]  Xia Han,et al.  The mechanisms of differential sensitivity to an insulin-like growth factor-1 receptor inhibitor (BMS-536924) and rationale for combining with EGFR/HER2 inhibitors. , 2009, Cancer research.

[65]  G M Clark,et al.  Insulin-like growth factor-I receptors are overexpressed and predict a low risk in human breast cancer. , 1993, Cancer research.

[66]  D. Leroith,et al.  The role of the IGF system in cancer growth and metastasis: overview and recent insights. , 2007, Endocrine reviews.

[67]  A. Ullrich,et al.  Receptors for insulin and insulin-like growth factor-I can form hybrid dimers. Characterisation of hybrid receptors in transfected cells. , 1990, The Biochemical journal.

[68]  Zheng Yang,et al.  BMS-754807, a small molecule inhibitor of insulin-like growth factor-1R/IR , 2009, Molecular Cancer Therapeutics.

[69]  L. Klotz,et al.  Association of diet-induced hyperinsulinemia with accelerated growth of prostate cancer (LNCaP) xenografts. , 2007, Journal of the National Cancer Institute.

[70]  I. McCutcheon,et al.  The effects of insulin-like growth factors on tumorigenesis and neoplastic growth. , 2000, Endocrine reviews.