Journal Mobile Options
Table of Contents
Vol. 77, No. 6, 2009
Issue release date: February 2010

EGFR Signaling and Drug Discovery

Lurje G. · Lenz H.-J.
To view the fulltext, log in and/or choose pay-per-view option

Individual Users: Register with Karger Login Information

Please create your User ID & Password





Contact Information











I have read the Karger Terms and Conditions and agree.

To view the fulltext, please log in

To view the pdf, please log in

Abstract

Dysregulation of human epidermal growth factor receptor (ErbB/HER) pathways by over-expression or constitutive activation can promote tumor processes including angiogenesis and metastasis and is associated with poor prognosis in many human malignancies. In addition to cancer, ErbB signaling has also been implicated in cardiovascular and neurodegenerative diseases. Conversely, inhibition of ErbB pathways with targeted agents, such as monoclonal antibodies (MoAbs) or tyrosine kinase inhibitors (TKIs), blocks cell cycle progression, inhibits the production of pro-angiogenic factors and induces apoptosis in numerous in vitro and xenograft models. Accordingly, the ErbB receptor family with their most prominent members EGFR and HER-2 represents validated targets for anti-cancer therapy, and anti-ErbB MoAbs (cetuximab, panitumumab, and trastuzumab) and TKIs (gefitinib, erlotinib, and lapatinib) have now been approved for the treatment of advanced colorectal cancer, squamous cell carcinoma of the head and neck, advanced non-small-cell lung cancer, as well as pancreatic and breast cancer. Although results have been encouraging, more work remains to be done.



Copyright / Drug Dosage

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

References

  1. Scaltriti M, Baselga J: The epidermal growth factor receptor pathway: a model for targeted therapy. Clin Cancer Res 2006;12:5268–5272.
  2. Schlessinger J, Lemmon MA: Nuclear signaling by receptor tyrosine kinases: the first robin of spring. Cell 2006;127:45–48.
  3. Salomon DS, Brandt R, Ciardiello F, Normanno N: Epidermal growth factor-related peptides and their receptors in human malignancies. Crit Rev Oncol Hematol 1995;19:183–232.
  4. Hemming AW, Davis NL, Kluftinger A, Robinson B, Quenville NF, Liseman B, LeRiche J: Prognostic markers of colorectal cancer: an evaluation of DNA content, epidermal growth factor receptor, and Ki-67. J Surg Oncol 1992;51:147–152.
  5. Klapper LN, Kirschbaum MH, Sela M, Yarden Y: Biochemical and clinical implications of the ErbB/HER signaling network of growth factor receptors. Adv Cancer Res 2000;77:25–79.
  6. Mendelsohn J, Baselga J: Epidermal growth factor receptor targeting in cancer. Semin Oncol 2006;33:369–385.
  7. Hynes NE, Lane HA: ERBB receptors and cancer: the complexity of targeted inhibitors. Nat Rev Cancer 2005;5:341–354.
  8. Yarden Y, Sliwkowski MX: Untangling the ErbB signalling network. Nat Rev Mol Cell Biol 2001;2:127–137.
  9. Press MF, Lenz HJ: EGFR, HER2 and VEGF pathways: validated targets for cancer treatment. Drugs 2007;67:2045–2075.
  10. Burgess AW, Cho HS, Eigenbrot C, Ferguson KM, Garrett TP, Leahy DJ, Lemmon MA, Sliwkowski MX, Ward CW, Yokoyama S: An open-and-shut case? Recent insights into the activation of EGF/ErbB receptors. Mol Cell 2003;12:541–552.
  11. Dawson JP, Berger MB, Lin CC, Schlessinger J, Lemmon MA, Ferguson KM: Epidermal growth factor receptor dimerization and activation require ligand-induced conformational changes in the dimer interface. Mol Cell Biol 2005;25:7734–7742.
  12. Klein P, Mattoon D, Lemmon MA, Schlessinger J: A structure-based model for ligand binding and dimerization of EGF receptors. Proc Natl Acad Sci USA 2004;101:929–934.
  13. Lowenstein EJ, Daly RJ, Batzer AG, Li W, Margolis B, Lammers R, Ullrich A, Skolnik EY, Bar-Sagi D, Schlessinger J: The SH2 and SH3 domain-containing protein GRB2 links receptor tyrosine kinases to ras signaling. Cell 1992;70:431–442.
  14. Batzer AG, Rotin D, Urena JM, Skolnik EY, Schlessinger J: Hierarchy of binding sites for Grb2 and Shc on the epidermal growth factor receptor. Mol Cell Biol 1994;14:5192–5201.
  15. Hallberg B, Rayter SI, Downward J: Interaction of Ras and Raf in intact mammalian cells upon extracellular stimulation. J Biol Chem 1994;269:3913–3916.
  16. Liebmann C: Regulation of MAP kinase activity by peptide receptor signalling pathway: paradigms of multiplicity. Cell Signal 2001;13:777–785.
  17. Hill CS, Treisman R: Transcriptional regulation by extracellular signals: mechanisms and specificity. Cell 1995;80:199–211.
  18. Vivanco I, Sawyers CL: The phosphatidylinositol 3-kinase AKT pathway in human cancer. Nat Rev Cancer 2002;2:489–501.
  19. Carpenter CL, Auger KR, Chanudhuri M, Yoakim M, Schaffhausen B, Shoelson S, Cantley LC: Phosphoinositide 3-kinase is activated by phosphopeptides that bind to the SH2 domains of the 85-kDa subunit. J Biol Chem 1993;268:9478–9483.
  20. Yu J, Wjasow C, Backer JM: Regulation of the p85/p110α phosphatidylinositol 3′-kinase. Distinct roles for the N-terminal and C-terminal SH2 domains. J Biol Chem 1998;273:30199–30203.
  21. Yu J, Zhang Y, McIlroy J, Rordorf-Nikolic T, Orr GA, Backer JM: Regulation of the p85/p110 phosphatidylinositol 3′-kinase: stabilization and inhibition of the p110α catalytic subunit by the p85 regulatory subunit. Mol Cell Biol 1998;18:1379–1387.
  22. Stokoe D, Stephens LR, Copeland T, Gaffney PR, Reese CB, Painter GF, Holmes AB, McCormick F, Hawkins PT: Dual role of phosphatidylinositol-3,4,5-trisphosphate in the activation of protein kinase B. Science 1997;277:567–570.
  23. Andl CD, Mizushima T, Oyama K, Bowser M, Nakagawa H, Rustgi AK: EGFR-induced cell migration is mediated predominantly by the JAK-STAT pathway in primary esophageal keratinocytes. Am J Physiol Gastrointest Liver Physiol 2004;287:G1227–G1237.
  24. Kloth MT, Laughlin KK, Biscardi JS, Boerner JL, Parsons SJ, Silva CM: STAT5B, a mediator of synergism between c-Src and the epidermal growth factor receptor. J Biol Chem 2003;278:1671–1679.
  25. Darnell JE Jr: STATs and gene regulation. Science 1997;277:1630–1635.
  26. Zhong Z, Wen Z, Darnell JE Jr: Stat3: a STAT family member activated by tyrosine phosphorylation in response to epidermal growth factor and interleukin-6. Science 1994;264:95–98.
  27. Yu H, Jove R: The STATs of cancer – new molecular targets come of age. Nat Rev Cancer 2004;4:97–105.
  28. Bowman T, Garcia R, Turkson J, Jove R: STATs in oncogenesis. Oncogene 2000;19:2474–2488.
  29. Haura EB, Turkson J, Jove R: Mechanisms of disease: insights into the emerging role of signal transducers and activators of transcription in cancer. Nat Clin Pract Oncol 2005;2:315–324.
  30. Bromberg J: Stat proteins and oncogenesis. J Clin Invest 2002;109:1139–1142.
  31. Martin GS: Cell signaling and cancer. Cancer Cell 2003;4:167–174.
  32. Summy JM, Gallick GE: Treatment for advanced tumors: Src reclaims center stage. Clin Cancer Res 2006;12:1398–1401.
  33. Yeatman TJ: A renaissance for SRC. Nat Rev Cancer 2004;4:470–480.
  34. Leu TH, Maa MC: Functional implication of the interaction between EGF receptor and c-Src. Front Biosci 2003;8:s28–s38.
  35. Bianco R, Gelardi T, Damiano V, Ciardiello F, Tortora G: Rational bases for the development of EGFR inhibitors for cancer treatment. Int J Biochem Cell Biol 2007;39:1416–1431.
  36. Arteaga CL: The epidermal growth factor receptor: from mutant oncogene in nonhuman cancers to therapeutic target in human neoplasia. J Clin Oncol 2001;19:32S–40S.
  37. Baselga J: Why the epidermal growth factor receptor? The rationale for cancer therapy. Oncologist 2002;7(suppl 4):2–8.
  38. Fan Z, Baselga J, Masui H, Mendelsohn J: Antitumor effect of anti-epidermal growth factor receptor monoclonal antibodies plus cis-diamminedichloroplatinum on well established A431 cell xenografts. Cancer Res 1993;53:4637–4642.
  39. Karnes WE Jr, Weller SG, Adjei PN, Kottke TJ, Glenn KS, Gores GJ, Kaufmann SH: Inhibition of epidermal growth factor receptor kinase induces protease-dependent apoptosis in human colon cancer cells. Gastroenterology 1998;114:930–939.
  40. Wu X, Fan Z, Masui H, Rosen N, Mendelsohn J: Apoptosis induced by an anti-epidermal growth factor receptor monoclonal antibody in a human colorectal carcinoma cell line and its delay by insulin. J Clin Invest 1995;95:1897–1905.
  41. Milas L, Mason KA, Ang KK: Epidermal growth factor receptor and its inhibition in radiotherapy: in vivo findings. Int J Radiat Biol 2003;79:539–545.
  42. Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL: Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 1987;235:177–182.
  43. Slamon DJ, Godolphin W, Jones LA, Holt JA, Wong SG, Keith DE, Levin WJ, Stuart SG, Udove J, Ullrich A, et al: Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science 1989;244:707–712.
  44. Citri A, Yarden Y: EGF-ERBB signalling: towards the systems level. Nat Rev Mol Cell Biol 2006;7:505–516.
  45. Gschwind A, Fischer OM, Ullrich A: The discovery of receptor tyrosine kinases: targets for cancer therapy. Nat Rev Cancer 2004;4:361–370.
  46. De Larco JE, Reynolds R, Carlberg K, Engle C, Todaro GJ: Sarcoma growth factor from mouse sarcoma virus-transformed cells. Purification by binding and elution from epidermal growth factor receptor-rich cells. J Biol Chem 1980;255:3685–3690.
  47. Downward J, Yarden Y, Mayes E, Scrace G, Totty N, Stockwell P, Ullrich A, Schlessinger J, Waterfield MD: Close similarity of epidermal growth factor receptor and v-erb-B oncogene protein sequences. Nature 1984;307:521–527.
  48. Gill GN, Kawamoto T, Cochet C, Le A, Sato JD, Masui H, McLeod C, Mendelsohn J: Monoclonal anti-epidermal growth factor receptor antibodies which are inhibitors of epidermal growth factor binding and antagonists of epidermal growth factor-stimulated tyrosine protein kinase activity. J Biol Chem 1984;259:7755–7760.
  49. Kawamoto T, Sato JD, Le A, Polikoff J, Sato GH, Mendelsohn J: 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 USA 1983;80:1337–1341.
  50. Masui H, Kawamoto T, Sato JD, Wolf B, Sato G, Mendelsohn J: Growth inhibition of human tumor cells in athymic mice by anti-epidermal growth factor receptor monoclonal antibodies. Cancer Res 1984;44:1002–1007.
  51. Sato JD, Kawamoto T, Le AD, Mendelsohn J, Polikoff J, Sato GH: Biological effects in vitro of monoclonal antibodies to human epidermal growth factor receptors. Mol Biol Med 1983;1:511–529.
  52. Crone SA, Zhao YY, Fan L, Gu Y, Minamisawa S, Liu Y, Peterson KL, Chen J, Kahn R, Condorelli G, Ross J Jr, Chien KR, Lee KF: ErbB2 is essential in the prevention of dilated cardiomyopathy. Nat Med 2002;8:459–465.
  53. Rohrbach S, Yan X, Weinberg EO, Hasan F, Bartunek J, Marchionni MA, Lorell BH: Neuregulin in cardiac hypertrophy in rats with aortic stenosis. Differential expression of erbB2 and erbB4 receptors. Circulation 1999;100:407–412.
  54. Iwakura Y, Piao YS, Mizuno M, Takei N, Kakita A, Takahashi H, Nawa H: Influences of dopaminergic lesion on epidermal growth factor-ErbB signals in Parkinson’s disease and its model: neurotrophic implication in nigrostriatal neurons. J Neurochem 2005;93:974–983.
  55. Higa GM, Abraham J: Lapatinib in the treatment of breast cancer. Expert Rev Anticancer Ther 2007;7:1183–1192.
  56. Gatta G, Faivre J, Capocaccia R, Ponz de Leon M: Survival of colorectal cancer patients in Europe during the period 1978–1989. Eur J Cancer 1998;34:2176–2183.
  57. Bleeker WK, Lammerts van Bueren JJ, van Ojik HH, Gerritsen AF, Pluyter M, Houtkamp M, Halk E, Goldstein J, Schuurman J, van Dijk MA, van de Winkel JG, Parren PW: Dual mode of action of a human anti-epidermal growth factor receptor monoclonal antibody for cancer therapy. J Immunol 2004;173:4699–4707.
  58. Kim ES, Khuri FR, Herbst RS: Epidermal growth factor receptor biology (IMC-C225). Curr Opin Oncol 2001;13:506–513.
  59. Cunningham D, Humblet Y, Siena S, Khayat D, Bleiberg H, Santoro A, Bets D, Mueser M, Harstrick A, Verslype C, Chau I, Van Cutsem E: Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 2004;351:337–345.
  60. Lenz HJ, Van Cutsem E, Khambata-Ford S, Mayer RJ, Gold P, Stella P, Mirtsching B, Cohn AL, Pippas AW, Azarnia N, Tsuchihashi Z, Mauro DJ, Rowinsky EK: Multicenter phase II and translational study of cetuximab in metastatic colorectal carcinoma refractory to irinotecan, oxaliplatin, and fluoropyrimidines. J Clin Oncol 2006;24:4914–4921.
  61. Saltz LB, Meropol NJ, Loehrer PJ Sr, Needle MN, Kopit J, Mayer RJ: Phase II trial of cetuximab in patients with refractory colorectal cancer that expresses the epidermal growth factor receptor. J Clin Oncol 2004;22:1201–1208.
  62. Van Cutsem E, Kohne CH, Hitre E, Zaluski J, Chang Chien CR, Makhson A, D’Haens G, Pinter T, Lim R, Bodoky G, Roh JK, Folprecht G, Ruff P, Stroh C, Tejpar S, Schlichting M, Nippgen J, Rougier P: Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med 2009;360:1408–1417.
  63. Bokemeyer C, Bondarenko I, Hartmann J, De Braud F, Volovat C, Nippgen J, Stroh C, Celik I, Koralewski P: KRAS status and efficacy of first-line treatment of patients with metastatic colorectal cancer (mCRC) with FOLFOX with or without cetuximab: the OPUS experience. Chicago, ASCO Annual Meeting, 2008. J Clin Oncol 2008;26(suppl):abstr 4000.
  64. Tol J, Koopman M, Cats A, Rodenburg CJ, Creemers GJ, Schrama JG, Erdkamp FL, Vos AH, van Groeningen CJ, Sinnige HA, Richel DJ, Voest EE, Dijkstra JR, Vink-Borger ME, Antonini NF, Mol L, van Krieken JH, Dalesio O, Punt CJ: Chemotherapy, bevacizumab, and cetuximab in metastatic colorectal cancer. N Engl J Med 2009;360:563–572.
  65. Doody JF, Wang Y, Patel SN, Joynes C, Lee SP, Gerlak J, Rolser RL, Li Y, Steiner P, Bassi R, Hicklin DJ, Hadari YR: Inhibitory activity of cetuximab on epidermal growth factor receptor mutations in non small cell lung cancers. Mol Cancer Ther 2007;6:2642–2651.
  66. Steiner P, Joynes C, Bassi R, Wang S, Tonra JR, Hadari YR, Hicklin DJ: Tumor growth inhibition with cetuximab and chemotherapy in non-small cell lung cancer xenografts expressing wild-type and mutated epidermal growth factor receptor. Clin Cancer Res 2007;13:1540–1551.
  67. Perez-Torres M, Guix M, Gonzalez A, Arteaga CL: Epidermal growth factor receptor (EGFR) antibody down-regulates mutant receptors and inhibits tumors expressing EGFR mutations. J Biol Chem 2006;281:40183–40192.
  68. Cascinu S, Berardi R, Labianca R, Siena S, Falcone A, Aitini E, Barni S, Di Costanzo F, Dapretto E, Tonini G, Pierantoni C, Artale S, Rota S, Floriani I, Scartozzi M, Zaniboni A: Cetuximab plus gemcitabine and cisplatin compared with gemcitabine and cisplatin alone in patients with advanced pancreatic cancer: a randomised, multicentre, phase II trial. Lancet Oncol 2008;9:39–44.
  69. Bonner JA, Harari PM, Giralt J, Azarnia N, Shin DM, Cohen RB, Jones CU, Sur R, Raben D, Jassem J, Ove R, Kies MS, Baselga J, Youssoufian H, Amellal N, Rowinsky EK, Ang KK: Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med 2006;354:567–578.
  70. Herceptin® (trastuzumab) (package insert). South San Fancisco, Genentech I, 2004.
  71. Hommelgaard AM, Lerdrup M, van Deurs B: Association with membrane protrusions makes ErbB2 an internalization-resistant receptor. Mol Biol Cell 2004;15:1557–1567.
  72. Clynes RA, Towers TL, Presta LG, Ravetch JV: Inhibitory Fc receptors modulate in vivo cytoxicity against tumor targets. Nat Med 2000;6:443–446.
  73. Schneider JW, Chang AY, Rocco TP: Cardiotoxicity in signal transduction therapeutics: erbB2 antibodies and the heart. Semin Oncol 2001;28:18–26.
  74. Foon KA, Yang XD, Weiner LM, Belldegrun AS, Figlin RA, Crawford J, Rowinsky EK, Dutcher JP, Vogelzang NJ, Gollub J, Thompson JA, Schwartz G, Bukowski RM, Roskos LK, Schwab GM: Preclinical and clinical evaluations of ABX-EGF, a fully human anti-epidermal growth factor receptor antibody. Int J Radiat Oncol Biol Phys 2004;58:984–990.
  75. Sridhar SS, Seymour L, Shepherd FA: Inhibitors of epidermal-growth-factor receptors: a review of clinical research with a focus on non-small-cell lung cancer. Lancet Oncol 2003;4:397–406.
  76. Yang XD, Jia XC, Corvalan JR, Wang P, Davis CG: Development of ABX-EGF, a fully human anti-EGF receptor monoclonal antibody, for cancer therapy. Crit Rev Oncol Hematol 2001;38:17–23.
  77. Hoy SM, Wagstaff AJ: Panitumumab: in the treatment of metastatic colorectal cancer. Drugs 2006;66:2005–2014, discussion 2015–2016.
  78. Van Cutsem E, Peeters M, Siena S, Humblet Y, Hendlisz A, Neyns B, Canon JL, Van Laethem JL, Maurel J, Richardson G, Wolf M, Amado RG: Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer. J Clin Oncol 2007;25:1658–1664.
  79. Fukuoka M, Yano S, Giaccone G, Tamura T, Nakagawa K, Douillard JY, Nishiwaki Y, Vansteenkiste J, Kudoh S, Rischin D, Eek R, Horai T, Noda K, Takata I, Smit E, Averbuch S, Macleod A, Feyereislova A, Dong RP, Baselga J: Multi-institutional randomized phase II trial of gefitinib for previously treated patients with advanced non-small-cell lung cancer (The IDEAL 1 Trial) [corrected]. J Clin Oncol 2003;21:2237–2246.
  80. Kris MG, Natale RB, Herbst RS, Lynch TJ Jr, Prager D, Belani CP, Schiller JH, Kelly K, Spiridonidis H, Sandler A, Albain KS, Cella D, Wolf MK, Averbuch SD, Ochs JJ, Kay AC: Efficacy of gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in symptomatic patients with non-small cell lung cancer: a randomized trial. JAMA 2003;290:2149–2158.
  81. Popat S, Hubner R, Houlston RS: Systematic review of microsatellite instability and colorectal cancer prognosis. J Clin Oncol 2005;23:609–618.
  82. Giaccone G, Herbst RS, Manegold C, Scagliotti G, Rosell R, Miller V, Natale RB, Schiller JH, Von Pawel J, Pluzanska A, Gatzemeier U, Grous J, Ochs JS, Averbuch SD, Wolf MK, Rennie P, Fandi A, Johnson DH: Gefitinib in combination with gemcitabine and cisplatin in advanced non-small-cell lung cancer: a phase III trial – INTACT 1. J Clin Oncol 2004;22:777–784.
  83. Herbst RS, Giaccone G, Schiller JH, Natale RB, Miller V, Manegold C, Scagliotti G, Rosell R, Oliff I, Reeves JA, Wolf MK, Krebs AD, Averbuch SD, Ochs JS, Grous J, Fandi A, Johnson DH: Gefitinib in combination with paclitaxel and carboplatin in advanced non-small-cell lung cancer: a phase III trial – INTACT 2. J Clin Oncol 2004;22:785–794.
  84. Lynch TJ, Bell DW, Sordella R, Gurubhagavatula S, Okimoto RA, Brannigan BW, Harris PL, Haserlat SM, Supko JG, Haluska FG, Louis DN, Christiani DC, Settleman J, Haber DA: Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 2004;350:2129–2139.
  85. Carethers JM, Chauhan DP, Fink D, Nebel S, Bresalier RS, Howell SB, Boland CR: Mismatch repair proficiency and in vitro response to 5-fluorouracil. Gastroenterology 1999;117:123–131.
  86. Shepherd FA, Rodrigues Pereira J, Ciuleanu T, Tan EH, Hirsh V, Thongprasert S, Campos D, Maoleekoonpiroj S, Smylie M, Martins R, van Kooten M, Dediu M, Findlay B, Tu D, Johnston D, Bezjak A, Clark G, Santabarbara P, Seymour L: Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med 2005;353:123–132.
  87. Moore MJ, Goldstein D, Hamm J, Figer A, Hecht JR, Gallinger S, Au HJ, Murawa P, Walde D, Wolff RA, Campos D, Lim R, Ding K, Clark G, Voskoglou-Nomikos T, Ptasynski M, Parulekar W: Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 2007;25:1960–1966.
  88. Rusnak DW, Alligood KJ, Mullin RJ, Spehar GM, Arenas-Elliott C, Martin AM, Degenhardt Y, Rudolph SK, Haws TF Jr, Hudson-Curtis BL, Gilmer TM: Assessment of epidermal growth factor receptor (EGFR, ErbB1) and HER2 (ErbB2) protein expression levels and response to lapatinib (Tykerb, GW572016) in an expanded panel of human normal and tumour cell lines. Cell Prolif 2007;40:580–594.
  89. Wood ER, Truesdale AT, McDonald OB, Yuan D, Hassell A, Dickerson SH, Ellis B, Pennisi C, Horne E, Lackey K, Alligood KJ, Rusnak DW, Gilmer TM, Shewchuk L: A unique structure for epidermal growth factor receptor bound to GW572016 (lapatinib): relationships among protein conformation, inhibitor off-rate, and receptor activity in tumor cells. Cancer Res 2004;64:6652–6659.
  90. Konecny GE, Pegram MD, Venkatesan N, Finn R, Yang G, Rahmeh M, Untch M, Rusnak DW, Spehar G, Mullin RJ, Keith BR, Gilmer TM, Berger M, Podratz KC, Slamon DJ: Activity of the dual kinase inhibitor lapatinib (GW572016) against HER-2-overexpressing and trastuzumab-treated breast cancer cells. Cancer Res 2006;66:1630–1639.
  91. Camp ER, Summy J, Bauer TW, Liu W, Gallick GE, Ellis LM: Molecular mechanisms of resistance to therapies targeting the epidermal growth factor receptor. Clin Cancer Res 2005;11:397–405.
  92. Prenen H, De Schutter J, Jacobs B, De Roock W, Biesmans B, Claes B, Lambrechts D, Van Cutsem E, Tejpar S: PIK3CA mutations are not a major determinant of resistance to the epidermal growth factor receptor inhibitor cetuximab in metastatic colorectal cancer. Clin Cancer Res 2009;15:3184–3188.
  93. Sartore-Bianchi A, Martini M, Molinari F, Veronese S, Nichelatti M, Artale S, Di Nicolantonio F, Saletti P, De Dosso S, Mazzucchelli L, Frattini M, Siena S, Bardelli A: PIK3CA mutations in colorectal cancer are associated with clinical resistance to EGFR-targeted monoclonal antibodies. Cancer Res 2009;69:1851–1857.
  94. Di Nicolantonio F, Martini M, Molinari F, Sartore-Bianchi A, Arena S, Saletti P, De Dosso S, Mazzucchelli L, Frattini M, Siena S, Bardelli A: Wild-type BRAF is required for response to panitumumab or cetuximab in metastatic colorectal cancer. J Clin Oncol 2008;26:5705–5712.
  95. Vallbohmer D, Zhang W, Gordon M, Yang DY, Yun J, Press OA, Rhodes KE, Sherrod AE, Iqbal S, Danenberg KD, Groshen S, Lenz HJ: Molecular determinants of cetuximab efficacy. J Clin Oncol 2005;23:3536–3544.
  96. Zhang W, Gordon M, Press OA, Rhodes K, Vallbohmer D, Yang DY, Park D, Fazzone W, Schultheis A, Sherrod AE, Iqbal S, Groshen S, Lenz HJ: Cyclin D1 and epidermal growth factor polymorphisms associated with survival in patients with advanced colorectal cancer treated with cetuximab. Pharmacogenet Genomics 2006;16:475–483.
  97. Zhang W, Gordon M, Schultheis AM, Yang DY, Nagashima F, Azuma M, Chang HM, Borucka E, Lurje G, Sherrod AE, Iqbal S, Groshen S, Lenz HJ: FCGR2A and FCGR3A polymorphisms associated with clinical outcome of epidermal growth factor receptor expressing metastatic colorectal cancer patients treated with single-agent cetuximab. J Clin Oncol 2007;25:3712–3718.
  98. Lurje G, Nagashima F, Zhang W, Yang D, Chang HM, Gordon MA, El-Khoueiry A, Husain H, Wilson PM, Ladner RD, Mauro DJ, Langer C, Rowinsky EK, Lenz HJ: Polymorphisms in cyclooxygenase-2 and epidermal growth factor receptor are associated with progression-free survival independent of K-ras in metastatic colorectal cancer patients treated with single-agent cetuximab. Clin Cancer Res 2008;14:7884–7895.
  99. Khambata-Ford S, Garrett CR, Meropol NJ, Basik M, Harbison CT, Wu S, Wong TW, Huang X, Takimoto CH, Godwin AK, Tan BR, Krishnamurthi SS, Burris HA 3rd, Poplin EA, Hidalgo M, Baselga J, Clark EA, Mauro DJ: Expression of epiregulin and amphiregulin and K-ras mutation status predict disease control in metastatic colorectal cancer patients treated with cetuximab. J Clin Oncol 2007;25:3230–3237.
  100. Karapetis CS, Khambata-Ford S, Jonker DJ, O’Callaghan CJ, Tu D, Tebbutt NC, Simes RJ, Chalchal H, Shapiro JD, Robitaille S, Price TJ, Shepherd L, Au HJ, Langer C, Moore MJ, Zalcberg JR: K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med 2008;359:1757–1765.
  101. Paez JG, Janne PA, Lee JC, Tracy S, Greulich H, Gabriel S, Herman P, Kaye FJ, Lindeman N, Boggon TJ, Naoki K, Sasaki H, Fujii Y, Eck MJ, Sellers WR, Johnson BE, Meyerson M: EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 2004;304:1497–1500.
  102. Personeni N, Fieuws S, Piessevaux H, De Hertogh G, De Schutter J, Biesmans B, De Roock W, Capoen A, Debiec-Rychter M, Van Laethem JL, Peeters M, Humblet Y, Van Cutsem E, Tejpar S: Clinical usefulness of EGFR gene copy number as a predictive marker in colorectal cancer patients treated with cetuximab: a fluorescent in situ hybridization study. Clin Cancer Res 2008;14:5869–5876.
  103. De Roock W, Piessevaux H, De Schutter J, Janssens M, De Hertogh G, Personeni N, Biesmans B, Van Laethem JL, Peeters M, Humblet Y, Van Cutsem E, Tejpar S: KRAS wild-type state predicts survival and is associated to early radiological response in metastatic colorectal cancer treated with cetuximab. Ann Oncol 2008;19:508–515.
  104. Di Fiore F, Blanchard F, Charbonnier F, Le Pessot F, Lamy A, Galais MP, Bastit L, Killian A, Sesboue R, Tuech JJ, Queuniet AM, Paillot B, Sabourin JC, Michot F, Michel P, Frebourg T: Clinical relevance of KRAS mutation detection in metastatic colorectal cancer treated by cetuximab plus chemotherapy. Br J Cancer 2007;96:1166–1169.
  105. Lievre A, Bachet JB, Boige V, Cayre A, Le Corre D, Buc E, Ychou M, Bouche O, Landi B, Louvet C, Andre T, Bibeau F, Diebold MD, Rougier P, Ducreux M, Tomasic G, Emile JF, Penault-Llorca F, Laurent-Puig P: KRAS mutations as an independent prognostic factor in patients with advanced colorectal cancer treated with cetuximab. J Clin Oncol 2008;26:374–379.
  106. Chakravarti A, Loeffler JS, Dyson NJ: Insulin-like growth factor receptor I mediates resistance to anti-epidermal growth factor receptor therapy in primary human glioblastoma cells through continued activation of phosphoinositide 3-kinase signaling. Cancer Res 2002;62:200–207.
  107. Lu Y, Zi X, Zhao Y, Mascarenhas D, Pollak M: Insulin-like growth factor-I receptor signaling and resistance to trastuzumab (Herceptin). J Natl Cancer Inst 2001;93:1852–1857.
  108. Motzer RJ, Escudier B, Oudard S, Hutson TE, Porta C, Bracarda S, Grunwald V, Thompson JA, Figlin RA, Hollaender N, Urbanowitz G, Berg WJ, Kay A, Lebwohl D, Ravaud A: Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet 2008;372:449–456.
  109. Talpaz M, Shah NP, Kantarjian H, Donato N, Nicoll J, Paquette R, Cortes J, O’Brien S, Nicaise C, Bleickardt E, Blackwood-Chirchir MA, Iyer V, Chen TT, Huang F, Decillis AP, Sawyers CL: Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias. N Engl J Med 2006;354:2531–2541.
  110. Geng L, Tan J, Himmelfarb E, Schueneman A, Niermann K, Brousal J, Fu A, Cuneo K, Kesicki EA, Treiberg J, Hayflick JS, Hallahan DE: A specific antagonist of the p110δ catalytic component of phosphatidylinositol 3′-kinase, IC486068, enhances radiation-induced tumor vascular destruction. Cancer Res 2004;64:4893–4899.
  111. Garcia A, Rosen L, Cunningham C, Nemunaitis J, Li C, Rulewski N, Dovholuk A, Savage R, Chan T, Bukowksi R, Mekhail T: Phase 1 study of ARQ 197, a selective inhibitor of the c-Met RTK in patients with metastatic solid tumors reaches recommended phase 2 dose. Chicago, ASCO Annual Meeting, 2007. J Clin Oncol 2007;25(suppl):abstr 3525.


Pay-per-View Options
Direct payment This item at the regular price: USD 38.00
Payment from account With a Karger Pay-per-View account (down payment USD 150) you profit from a special rate for this and other single items.
This item at the discounted price: USD 26.50