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Receptor Tyrosine Kinases as Targets for Cancer Therapy Development

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Part of the book series: Research and Perspectives in Endocrine Interactions ((RPEI))

Summary

Receptor tyrosine kinases (RTKs) are membrane-spanning proteins that possess a ligand-controlled intracellular kinase activity. They regulate a wide variety of cellular processess as diverse as cell proliferation, apoptosis or cell migration. Consequently, dysregulation of RTKs due to overexpression, mutation or autocrine stimulation has been causally linked to cancer development and progression. The advent of molecular cloning allowed the elucidationof the primary structure of the first RTK, the EGFR. Subsequent research in this field led to tremendous advances in understanding molecular signalling processes governing both physiological and pathophysiological behaviour of cells. These discoveries paved the way for the development of target-specific cancer therapeutics and opened up a new era of molecular targeted approaches in the treatment of human cancer. The approval of monoclonal antibodies such as Herceptin© for the treatment of breast cancer or small molecule inhibitors such as Gleevec© for gastrointestinal stromal tumors underlines both the power and success of this novel strategy.

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References

  • Agus DB, Akita RW, Fox WD, Lewis GD, Higgins B, Pisacane PI, Lofgren JA, Tindell C, Maiese K, Scher HI, Sliwkowski MX (2002) Targeting ligand-activated ErbB2 signaling inhibits breast and prostate tumor growth. Cancer Cell 2:127–137

    Article  PubMed  CAS  Google Scholar 

  • Bardelli A, Parsons DW, Silliman N, Ptak J, Szabo S, Saha S, Markowitz S, Willson JK, Parmigiani G, Kinzler KW, Vogelstein B, Velculescu VE (2003) Mutational analysis of the tyrosine kinome in colorectal cancers. Science 300:949

    Article  PubMed  CAS  Google Scholar 

  • Blume-Jensen P, Hunter T (2001) Oncogenic kinase signalling. Nature 411: 355–365

    Article  PubMed  CAS  Google Scholar 

  • Buchdunger E, Cioffi CL, Law N, Stover D, Ohno-Jones S, Druker BJ, Lydon NB (2000) Abl proteintyrosine kinase inhibitor STI571 inhibits in vitro signal transduction mediated by c-kit and platelet-derived growth factor receptors. J Pharmacol Exp Ther 295:139–145

    PubMed  CAS  Google Scholar 

  • Chiu IM, Reddy EP, Givol D, Robbins KC, Tronick SR, Aaronson SA (1984) Nucleotide sequence analysis identifies the human c-sis proto-oncogene as a structural gene for platelet-derived growth factor. Cell 37:123–129

    Article  PubMed  CAS  Google Scholar 

  • Coussens L, Yang-Feng TL, Liao YC, Chen E, Gray A, McGrath J, Seeburg PH, Libermann TA, Schlessinger J, Francke U, Ullrich A (1985) Tyrosine kinase receptor with extensive homology to EGF receptor shares chromosomal location with neu Oncogene. Science 230:1132–1139

    PubMed  CAS  Google Scholar 

  • Coussens L, Van Beveren C, Smith D, Chen E, Mitchell RL, Isacke CM, Verma IM, Ullrich A (1986) Structural alteration of viral homologue of receptor proto-oncogene fms at carboxyl terminus. Nature 320:277–280

    Article  PubMed  CAS  Google Scholar 

  • Derynck R, Roberts AB, Winkler ME, Chen EY, Goeddel DV (1984) Human transforming growth factor-alpha:precursor structure and expression in E. coli. Cell 38:287–297

    Article  PubMed  CAS  Google Scholar 

  • de Vries C, Escobedo JA, Ueno H, Houck K, Ferrara N, Williams LT (1992) The fms-like tyrosine kinase, a receptor for vascular endothelial growth factor. Science 255:989–991

    PubMed  Google Scholar 

  • Downward J, Yarden Y, Mayes E, Scrace G, Totty N, Stockwell P, Ullrich A, Schlessinger J, Waterfield MD (1984) Close similarity of epidermal growth factor receptor and v-erb-Boncogene protein sequences. Nature 307:521–527

    Article  PubMed  CAS  Google Scholar 

  • Drebin JA, Stern DF, Link VC, Weinberg RA, Greene MI (1984) Monoclonal antibodies identify a cell-surface antigen associated with an activated cellular oncogene. Nature 312:545–548

    Article  PubMed  CAS  Google Scholar 

  • Druker BJ, Tamura S, Buchdunger E, Ohno S, Segal GM, Fanning S, Zimmermann J, Lydon NB (1996) Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells. Nat Med 2:561–566

    Article  PubMed  CAS  Google Scholar 

  • Dull TJ, Gray A, Hayflick JS, Ullrich A (1984) Insulin-like growth factor II precursor gene organization in relation to insulin gene family. Nature 310: 777–781

    Article  PubMed  CAS  Google Scholar 

  • Ebina Y, Ellis L, Jarnagin K, Edery M, Graf L, Clauser E, Ou JH, Masiarz F, Kan YW, Goldfine ID, Roth RA, Rutter WJ (1985) The human insulin receptor cDNA:the structural basis for hormone-activated transmembrane signalling. Cell 40:747–758

    Article  PubMed  CAS  Google Scholar 

  • Fendly BM, Winget M, Hudziak RM, Lipari MT, Napier MA, Ullrich A (1990) Characterization of murine monoclonal antibodies reactive to either the human epidermal growth factor receptor or HER2/neu gene product. Cancer Res 50:1550–1558

    PubMed  CAS  Google Scholar 

  • Ferrara N (2002) VEGF and the quest for tumour angiogenesis factors. Nat Rev Cancer 2:795–803

    Article  PubMed  CAS  Google Scholar 

  • Folkman J (1971) Tumor angiogenesis:therapeutic implications. New Engl J Med 285:1182–1186

    Article  PubMed  CAS  Google Scholar 

  • Fong GH, Rossant J, Gertsenstein M, Breitman ML (1995) Role of the Flt-1 receptor tyrosine kinase in regulating the assembly of vascular endothelium. Nature 376:66–70

    Article  PubMed  CAS  Google Scholar 

  • Fong TA, Shawver LK, Sun L, Tang C, App H, Powell TJ, Kim YH, Schreck R, Wang X, Risau W, Ullrich A, Hirth KP, McMahon G (1999) SU5416 is a potent and selective inhibitor of the vascular endothelial growth factor receptor (Flk-1/KDR) that inhibits tyrosine kinase catalysis, tumor vascularization, and growth of multiple tumor types. Cancer Res 59:99–106

    PubMed  CAS  Google Scholar 

  • Fry DW, Kraker AJ, McMichael A, Ambroso LA, Nelson JM, Leopold WR, Connors RW, Bridges AJ (1994) A specific inhibitor of the epidermal growth factor receptor tyrosine kinase. Science 265:1093–1095

    PubMed  CAS  Google Scholar 

  • Gorre ME, Mohammed M, Ellwood K, Hsu N, Paquette R, Rao PN, Sawyers CL (2001) Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification. Science 293:876–880

    Article  PubMed  CAS  Google Scholar 

  • Gray A, Dull TJ, Ullrich A (1983) Nucleotide sequence of epidermal growth factor cDNA predicts a 128,000-molecular weight protein precursor. Nature 303:722–725

    Article  PubMed  CAS  Google Scholar 

  • Heinrich MC, Corless CL, Demetri GD Blanke CD, von Mehren M, Joensuu H, McGreevey LS, Chen CJ, Van den Abbeele AD, Druker BJ, Kiese B, Eisenberg B, Roberts PJ, Singer S, Fletcher CD, Silberman S, Dimitrijevic S, Fletcher JA (2003) Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor. J Clin Oncol 21:4342–4349

    Article  PubMed  CAS  Google Scholar 

  • Honegger AM, Dull TJ, Felder S, Van Obberghen E, Bellot F, Szapary D, Schmidt A, Ullrich A, Schlessinger J (1987) Point mutation at the ATP binding site of EGF receptor abolishes protein-tyrosine kinase activity and alters cellular routing. Cell 51:199–209

    Article  PubMed  CAS  Google Scholar 

  • Honegger AM, Szapary D, Schmidt A, Lyall R, Van Obberghen E, Dull TJ, Ullrich A, Schlessinger J (1987) Amutant epidermal growth factor receptor with defective protein tyrosine kinase is unable to stimulate proto-oncogene expression and DNA synthesis. Mol Cell Biol 7 4568–4571

    PubMed  CAS  Google Scholar 

  • Hudziak RM, Lewis GD, Winget M, Fendly BM, Shepard HM, Ullrich A (1989) p185HER2 monoclonal antibody has antiproliferative effects in vitro and sensitizes human breast tumor cells to tumor necrosis factor. Mol Cell Biol 9:1165–1172

    PubMed  CAS  Google Scholar 

  • Humphrey PA, Wong AJ, Vogelstein B, Zalutsky MR, Fuler GN, Archer GE, Friedmann HS, Kwatra MM, Bigner SH, Bigner DD (1990) Anti-synthetic peptide antibody reacting at the fusion junction of deletion-mutant epidermal growth factor receptors in human glioblastoma. Proc Natl Acad Sci USA 87:4207–4211

    Article  PubMed  CAS  Google Scholar 

  • Itakura K, Hirose T, Crea R, Riggs AD, Heyneker HL, Bolivar F, Boyer HW (1977) Expression in Escherichia coli of a chemically synthesized gene for the hormone somatostatin. Science 198:1056–1063

    PubMed  CAS  Google Scholar 

  • Joensuu H, Roberts PJ, Sarlomo-Rikala M, Andersson LC, Tervahartiala P, Tuveson D, Silberman S, Capdeville R, Dimitrijevic S, Druker B, Demetri GD (2001) Effect of the tyrosine kinase inhibitor STI571 in a patient with a metastatic gastrointestinal stromal tumor. N Engl J Med 344:1052–1056

    Article  PubMed  CAS  Google Scholar 

  • Johnsson A, Heldin CH, Wasteson A, Westermark B, Deuel TF, Huang JS, Seeburg PH, Gray A, Ullrich A, Scrace G, Stroobant P, Waterfield MD (1984) The c-sis gene encodes a precursor of the B chain of platelet-derived growth factor. Embo J 3:921–928

    PubMed  CAS  Google Scholar 

  • Kawamoto T, Sato JD, Le A, Polikoff J, Sato GH, Mendelsohn J (1983) Growth stimulation of A431 cells by epidermal growth factor:identification of high-affinity receptors for epidermal growth factor by an anti-receptor monoclonal antibody. Proc Natl Acad Sci U S A 80:1337–1341

    Article  PubMed  CAS  Google Scholar 

  • Kim KJ, Li B, Winer J, Armanini M, Gillett N, Phillips HS, Ferrara N (1993) Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumour growth in vivo. Nature 362:841–844

    Article  PubMed  CAS  Google Scholar 

  • King CR, Kraus MH, Aaronson SA (1985) Amplification of a novel v-erbB-related gene in a human mammary carcinoma. Science 229:974–6

    PubMed  CAS  Google Scholar 

  • Malden LT, Novak U, Kaye AH, Burgess AW (1988) Selective amplification of the cytoplasmic domain of the epidermal growth factor receptor gene in glioblastoma multiforme. Cancer Res 48:2711–2714

    PubMed  CAS  Google Scholar 

  • Margolis B, Rhee SG, Felder S, Mervic M, Lyall R, Levitzki A, Ullrich A, Zilberstein A, Schlessinger J (1989) EGF induces tyrosine phosphorylation of phospholipase C-II:a potential mechanism for EGF receptor signaling. Cell 57:1101–1107

    Article  PubMed  CAS  Google Scholar 

  • Martial JA, Hallewell RA, Baxter JD, Goodman HM (1979) Human growth hormone: complementary DNA cloning and expression in bacteria. Science 205:602–607

    PubMed  CAS  Google Scholar 

  • Millauer B, Wizigmann-Voos S, Schnurch H, Martinez R, Moller NP, Risau W, Ullrich A (1993) High affinity VEGF binding and developmental expression suggest Flk-1 as a major regulator of vasculogenesis and angiogenesis. Cell 72:835–846

    Article  PubMed  CAS  Google Scholar 

  • Millauer B, Shawver LK, Plate KH, Risau W, Ullrich A (1994) Glioblastoma growth inhibited in vivo by a dominant-negative Flk-1 mutant. Nature 367:576–579

    Article  PubMed  CAS  Google Scholar 

  • Millauer B, Longhi MP, Plate KH, Shawver LK, Risau W, Ullrich A, Strawn LM (1996) Dominant-negative inhibition of Flk-1 suppresses the growth of many tumor types in vivo. Cancer Res 56:1615–1620

    PubMed  CAS  Google Scholar 

  • O’Farrell AM, Abrams TJ, Yuen HA, Ngai TJ, Louie SG, Yee KW, Wong LM, Hong W, Lee LB, Town A, Smolich BD, Manning WC, Murray LJ, Heinrich MC, Cherrington JM (2003) SU11248 is a novel FLT3 tyrosine kinase inhibitor with potent activity in vitro and in vivo. Blood 101:3597–3605

    Article  PubMed  CAS  Google Scholar 

  • Osherov N, Levitzki A (1994) Epidermal-growth-factor-dependent activation of the src-family kinases. Eur J Biochem 225:1047–53

    Article  PubMed  CAS  Google Scholar 

  • Presta LG, Chen H, O’Connor SJ, Chisholm V, Meng YG, Krummen L, Winkler M, Ferrara N (1997) Humanization of an anti-vascular endothelial growth factor monoclonal antibody for the therapy of solid tumors and other disorders. Cancer Res 57:4593–4599

    PubMed  CAS  Google Scholar 

  • Quinn TP, Peters KG, De Vries C, Ferrara N, Williams LT (1993) Fetal liver kinase 1 is a receptor for vascular endothelial growth factor and is selectively expressed in vascular endothelium. Proc Natl Acad Sci USA 90:7533–7537

    Article  PubMed  CAS  Google Scholar 

  • Redemann N, Holzmann B, von Ruden T, Wagner EF, Schlessinger J, Ullrich A (1992) Antioncogenic activity of signalling-defective epidermal growth factor receptor mutants. Mol Cell Biol 12:491–498

    PubMed  CAS  Google Scholar 

  • Sato JD, Kawamoto T, Le AD, Mendelsohn J, Polikoff J, Sato GH (1983) Biological effects in vitro of monoclonal antibodies to human epidermal growth factor receptors. Mol Biol Med 1:511–529

    PubMed  CAS  Google Scholar 

  • Schechter AL, Stern DF, Vaidyanathan L, Decker SJ, Drebin JA, Greene MI, Weinberg RA (1984) The neu oncogene:an erb-B-related gene encoding a 185,000-Mr tumour antigen. Nature 312:513–516

    Article  PubMed  CAS  Google Scholar 

  • Scott J, Urdea M, Quiroga M, Sanchez-Pescador R, Fong N, Selby M, Rutter WJ, Bell GI (1983) Structure of a mouse submaxillary messenger RNA encoding epidermal growth factor and seven related proteins. Science 221:236–240

    PubMed  CAS  Google Scholar 

  • Shaheen RM, Davis DW, Liu W, Zebrowski BK, Wilson MR, Bucana CD, McConkey DJ, McMahon G, Ellis LM(1999) Antiangiogenic therapy targeting the tyrosine kinase receptor for vascular endothelial growth factor receptor inhibits the growth of colon cancer liver metastasis and induces tumor and endothelial cell apoptosis. Cancer Res 59:5412–5416

    PubMed  CAS  Google Scholar 

  • Shalaby F, Rossant J, Yamaguchi TP, Gertsenstein M, WU XF, Breitman ML, Schuh AC (1995) Failure of blood-island formation and vasculogenesis in Flk-1-deficient mice. Nature 376:62–66

    Article  PubMed  CAS  Google Scholar 

  • Sizeland AM, Burgess AW (1992) Anti-sense transforming growth factor alpha oligonucleotides inhibit autocrine stimulated proliferation of a colon carcinomacell line. Mol Biol Cell 3:1235–1243

    PubMed  CAS  Google Scholar 

  • Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL (1987) Human breast cancer: correlation of relapse and survival with amplificationof the HER-2/neu oncogene. Science 235:177–182

    PubMed  CAS  Google Scholar 

  • Slamon DJ, Godolphin W, Jones LA, Holt JA, Wong SG, Keith DE, Levin WJ, Stuart SG, Udove J, Ullrich A, Press MF (1989) Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science 244:707–712

    PubMed  CAS  Google Scholar 

  • Sures I, Goeddel DV, Gray A, Ullrich A (1980) Nucleotide sequence of human preproinsulin complementary DNA. Science 208:57–59

    PubMed  CAS  Google Scholar 

  • Terman BI, Dougher-Vermazen M, Carrion ME, Dimitrov D, Armellino DC, Gospodarowicz D, Bohlen P (1992) Identification of the KDR tyrosine kinase as a receptor for vascular endothelial cell growth factor. Biochem Biophys Res Commun 187:1579–1586

    Article  PubMed  CAS  Google Scholar 

  • Ullrich A, Shine J, Chirgwin J, Pictet R, Tischer E, Rutter WJ, Goodman HM (1977) Rat insulin genes:construction of plasmids containing the coding sequences. Science 196:1313–1319

    PubMed  CAS  Google Scholar 

  • Ullrich A, Gray A, Berman C, Dull TJ (1983) Human beta-nerve growth factor gene sequence highly homologous to that of mouse. Nature 303:821–825

    Article  PubMed  CAS  Google Scholar 

  • Ullrich A, Coussens L, Hayflick JS, Dull TJ, Gray A, Tam AW, Lee J, Yarden Y, Libermann TA, Schlessinger J, Downward J, Mayes ELV, Whittle N, Waterfield MD, Seeburg PH (1984) Human epidermal growth factor receptor cDNA sequence and aberrant expression of the amplified gene in A431 epidermoid carcinoma cells. Nature 309:418–425

    Article  PubMed  CAS  Google Scholar 

  • Ullrich A, Bell JR, Chen EY, Herrera R, Petruzzelli LM, Dull TJ, Gray A, Coussens L, Liao YC, Rosen OM, Ramachandran J (1985) Human insulin receptor and its relationship to the tyrosine kinase family of oncogenes. Nature 313:756–761

    Article  PubMed  CAS  Google Scholar 

  • Ullrich A, Gray A, Tam AW, Yang-Feng T, Tsubokawa M, Collins C, Henzel W, LeBon T, Kathuria S, Chen E, Jacobs S, Francke U, Ramachandran J, Fujita-Yamaguchi Y (1986) Insulin-like growth factor I receptor primary structure:comparison with insulin receptor suggests structural determinants that define functional specificity. Embo J 5:2503–2512

    PubMed  CAS  Google Scholar 

  • Wakeling AE, Barker AJ, Davies DH, Brown DS, Green LR, Cartlidge SA, Woodburn JR (1996) Specific inhibition of epidermal growth factor receptor tyrosine kinase by 4-anilinoquinazolines. Breast Cancer Res Treat 38:67–73

    Article  PubMed  CAS  Google Scholar 

  • Yaish P, Gazit A, Gilon C, Levitzki A (1988) Blocking of EGF-dependent cell proliferation by EGF receptor kinase inhibitors. Science 242:933–935

    PubMed  CAS  Google Scholar 

  • Yarden Y, Escobedo JA, Kuang WJ, Yang-Feng TL, Daniel TO, Tremble PM, Chen EY, Ando ME, Harkins RN, Francke U, Fried VA, Ullrich A, Williams LT (1986) Structure of the receptor for platelet-derived growth factor helps define a family of closely related growth factor receptors. Nature 323:226–232

    Article  PubMed  CAS  Google Scholar 

  • Yarden Y, Kuang WJ, Yang-Feng T, Coussens L, Munemitsu S, Dull TJ, Chen E, Schlessinger J, Francke U, Ullrich A (1987) Human proto-oncogene c-kit: a new cell surface receptor tyrosine kinase for an unidentified ligand. Embo J 6:3341–51

    PubMed  CAS  Google Scholar 

  • Yamamoto T, Hihara H, Nishida T, Kawai S, Toyoshima K (1983) A new avian erythroblastosis virus, AEV-H, carries erbB gene responsible for the induction of both erythroblastosis and sarcomas. Cell 34:225–232

    Article  PubMed  CAS  Google Scholar 

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© 2006 Springer-Verlag Berlin Heidelberg

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Gschwind, A., Fischer, O.M., Ullrich, A. (2006). Receptor Tyrosine Kinases as Targets for Cancer Therapy Development. In: Conn, M., Kordon, C., Christen, Y. (eds) Insights into Receptor Function and New Drug Development Targets. Research and Perspectives in Endocrine Interactions. Springer, Berlin, Heidelberg . https://doi.org/10.1007/3-540-34447-0_11

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