Cancer and Metastasis Reviews

, Volume 22, Issue 4, pp 301–307 | Cite as

Epidermal growth factor receptor family tyrosine kinases as signal integrators and therapeutic targets



Activating mutations, gene amplification and overexpression of human epidermal growth factor receptor (erbB or HER) family kinases have been implicated as integral contributors to a variety of cancers. However, there is increasing evidence that the HER family receptors propagate not only signals initiated by their own ligands but also those initiated by multiple other signaling pathways. Attenuation of HER family signaling is a developing strategy for the management of human malignancies and is the subject of a number of ongoing clinical trials. The purpose of this review is to provide a timely update of recent reports in the rapidly evolving area of HER family biology and the emerging integral role of these receptors in malignant transformation and as targets of cancer therapy.

EGFR HER signaling therapy cancer review 


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  1. 1.
    Graus-Porta D, Beerli RR, Daly JM, Hynes NE: ErbB-2, the preferred heterodimerization partner of all ErbB receptors, is a mediator of lateral signaling. EMBO J 16: 1647–55, 1997Google Scholar
  2. 2.
    Hulit J, Lee RJ, Russell RG, Pestell RG: ErbB-2-induced mammary tumor growth: The role of cyclin D1 and p27Kip1. Biochem Pharmacol 64: 827–836, 2002Google Scholar
  3. 3.
    Kumar R, Vadlamudi R: EGF family of growth factors. J Cli Ligand Assay 3: 233–238, 2000Google Scholar
  4. 4.
    deBono JS, Rowinsky EK: The ErbB receptor family: A therapeutic target for cancer. Trends in Molecular Medicine 8(4): S19-S26, 2002Google Scholar
  5. 5.
    Shawver LK, Slamon D, Ullrich A: Smart drugs: Tyrosine kinase inhibitors in cancer therapy. Cancer Cell 1: 117–123, 2002Google Scholar
  6. 6.
    Yarden Y, Sliwkowski MX: Untangling the ErbB signaling network. Nature Reviews Molecular Cell Biology 2: 127–137, 2001Google Scholar
  7. 7.
    Cho HS, Leahy DJ: Structure of the extracellular region of HER3 reveals an interdomain tether. Science 297: 1330–1333, 2002Google Scholar
  8. 8.
    Garrett TPJ, McKern NM, Lou MZ, Elleman TC, Adams TE, Lovrecz GO, Zhu HJ, Walker F, Frenkel MJ, Hoyne PA, Jorissen RN, Nice EC, Burgess AW, Ward CW: Crystal structure of a truncated epidermal growth factor receptor extracellular domain bound to transforming growth factor alpha. Cell 110: 763–773, 2002Google Scholar
  9. 9.
    Ogiso H, Ishitani R, Nureki O, Fukai S, Yamanaka M, Kim JH, Saito K, Sakamoto A, Inoue M, Shirouzu M, Yokoyama S: Crystal structure of the complex of human epidermal growth factor and receptor extracellular domains. Cell 110: 775–787, 2002Google Scholar
  10. 10.
    Schlessinger J: Ligand-induced, receptor-mediated dimerization and activation of EGF receptor. Cell 110: 669–672, 2002Google Scholar
  11. 11.
    Pai R, Soreghan B, Szabo IL, Pavelka M, Baatar D, Tarnawski AS: Prostaglandin E2 transactivates EGF receptor: at A novel mechanism for promoting colon cancer growth and gastrointestinal hypertrophy. Nature Medicine 8(3): 289–293, 2002Google Scholar
  12. 12.
    Vadlamudi R, Mandal M, Adam L, Steinbach G, Mendelsohn J, Kumar R: Regulation of cyclooxygenase-2 pathway by HER2 receptor. Oncogene 18(2): 305–14, 1999Google Scholar
  13. 13.
    Howe LR, Subbaramaiah K, Patel J, Masferrer JL, Deora A, Hudis C, Thaler HT, Muller WJ, Du BH, Brown AMC, Dannenberg AJ: Celecoxib, a selective cyclooxygenase 2 inhibitor, protects against human epidermal growth factor receptor 2 (HER-2)/ neu-induced breast cancer. Cancer Research 62(19): 5405–5407, 2002Google Scholar
  14. 14.
    Andreasen PA, Egelund R, Petersen HH: The plasminogen activation system in tumor growth, invasion, and metastasis. Cellular & Molecular Life Sciences 57: 25–40, 2000Google Scholar
  15. 15.
    Liu D, Ghiso JAA, Estrada Y, Ossowski L: EGFR is a transducer of the urokinase receptor initiated signal that is required for in vivo growth of a human carcinoma. Cancer Cell 1(5): 445–457, 2002Google Scholar
  16. 16.
    Golubovskaya V, Beviglia L, Xu LH, Earp HS, Craven R, Cance W: Dual inhibition of focal adhesion kinase and epidermal growth factor receptor pathways cooperatively induces death receptor-mediated apoptosis in human breast cancer cells. Journal of Biological Chemistry 277(41): 38978–38987, 2002Google Scholar
  17. 17.
    Xia L, Wang LJ, Chung AS, Ivanov SS, Ling MY, Dragoi AM, Platt A, Gilmer TM, Fu XY, Chin YE: Identification of both positive and negative domains within the epidermal growth factor receptor COOH-terminal region for signal transducer and activator of transcription (STAT) activation. Journal of Biological Chemistry 277(34): 30716–30723, 2002Google Scholar
  18. 18.
    Ren ZY, Schaefer TS: ErbB-2 activates Stat3 alpha in a Src-and JAK2-dependent manner. Journal of Biological Chemistry 277(41): 38486–38493, 2002Google Scholar
  19. 19.
    Kijima T, Niwa H, Steinman RA, Drenning SD, Gooding WE, Wentzel AL, Xi SC, Grandis JR: STAT3 activation abrogates growth factor dependence and contributes to head and neck squamous cell carcinoma tumor growth in vivo. Cell Growth & Differentiation 13(8) 355–362, 2002Google Scholar
  20. 20.
    Solbach C, Roller M, Ahr A, Loibl S, Nicoletti M, Stegmueller M, Kreysch HG, Knecht R, Kaufmann M: Anti-epidermal growth factor receptor-antibody therapy for treatment of breast cancer. International Journal of Cancer 101(4): 390–394, 2002Google Scholar
  21. 21.
    Agus DB, Akita RW, Fox WD, Lewis GD, Higgins B, Pisacane PI, Lofgren JA, Tindell C, Evans DP, Maiese K, Scher HI, Sliwkowski MX: Targeting ligand-activated ErbB2 signaling inhibits breast and prostate tumor growth. Cancer Cell 2(2): 127–137, 2002Google Scholar
  22. 22.
    Ng SSW, Tsao MS, Nicklee T, Hedley DW: Effects of the epidermal growth factor receptor inhibitor OSI-774, Tarceva, on downstream signaling pathways and apoptosis in human pancreatic adenocarcinoma. Molecular Cancer Therapeutics 1(10): 777–783, 2002Google Scholar
  23. 23.
    Mellinghoff IK, Tran C, Sawyers CL: Growth inhibitory effects of the dual ErbB1/ErbB2 tyrosine kinase inhibitor PKI-166 on human prostate cancer xenografts. Cancer Research 62(18): 5254–5259, 2002Google Scholar
  24. 24.
    Xia WL, Mullin RJ, Keith BR, Liu LH, Ma H, Rusnak DW, Owens G, Alligood KJ, Spector NL: Anti-tumor activity of GW572016: A dual tyrosine kinase inhibitor blocks EGF activation of EGFR/erbB2 and downstream Erk1/2 and AKT pathwaysOncogene. 21(41): 6255–6263, 2002Google Scholar
  25. 25.
    Allen LF, Lenehan PF, Eiseman IA, Elliot WL, Fry DW: Potential benefits of the irreversible pan-erbB inhibitor, CI-1033, in the treatment of breast cancer. Semin Oncol 29(Suppl 11): 11–21, 2002Google Scholar
  26. 26.
    Baselga J, Rischin D, Ranson M, Calvert H, Raymond E, Kieback DG, Kaye SB, Gianni L, Harris A, Bjork T, Averbuch SD, Feyereislova A, Swaisland H, Rojo F, Albanell J: Phase I safety, pharmacokinetic, and pharmacodynamic trial of ZD1839, a selective oral epidermal growth factor receptor tyrosine kinase inhibitor, in patients with five selected solid tumor types. Journal of Clinical Oncology 20(21): 4292–4302, 2002Google Scholar
  27. 27.
    Wakeling AE, Guy SP, Woodburn JR, Ashton SE, Curry BJ, Barker AJ, Gibson KH: ZD1839 (Iressa): An orally active inhibitor of epidermal growth factor signaling with potential for cancer therapy. Cancer Research 62(20): 5749–5754, 2002Google Scholar
  28. 28.
    Herbst RS, Maddox AM, Small EJ, Rothenberg L, Small EL, Rubin EH, Baselga J, Rojo F, Hong WK, Swaisland H, Averbuch SD, Ochs J, LoRusso PM: Selective oral epidermal growth factor receptor tyrosine kinase inhibitor ZD1839 is generally well-tolerated and has activity in nonsmall-cell lung cancer and other solid tumors: Results of a phase I trial. Journal of Clinical Oncology 20(18): 3815–3825, 2002Google Scholar
  29. 29.
    Twombly R: Despite Concerns, FDA panel backs EGFR inhibitor. JNCI 94(21): 1596–1597, 2002.Google Scholar
  30. 30.
    Dowsett M, Haper-Wynne C, Boeddinghaus I, Salter J, Hills M, Dixon M, Ebbs S, Gui G, Sacks N, Smith I: HER-2 amplification impedes the antiproliferative effects of hormone therapy in estrogen receptor positive primary breast cancer. Cancer Res 61: 8452–8458, 2001Google Scholar
  31. 31.
    Kumar R, Wang R-A, Mazumdar A, Talukder AH, Mandal M, Yang Z, Bagheri-yarmand R, Sahin A, Hortobagyi G, Adam L, Barnes CJ, Vadlamudi RK: A naturally occurring MTA1 variant sequesters oestrogen receptor-a in the cytoplasm. Nature 418: 654–657, 2002Google Scholar
  32. 32.
    Lee S, Yang WT, Lan KH, Sellappan S, Klos K, Hortobagyi G, Hung MC, Yu DH: Enhanced sensitization to Taxol-induced apoptosis by Herceptin pretreatment in ErbB2-overexpressing breast cancer cells. Cancer Research 62(20): 5703–5710, 2002Google Scholar
  33. 33.
    Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, Fleming T, Eirmann W, Wolter J, Pegram M, Baselga J, Norton L: Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 344: 783–792, 2001Google Scholar
  34. 34.
    Bagheri-Yarmand R, Vadlamudi RK, Wang RA, Mendelsohn J, Kumar R: Vascular endothelial growth factor upregulation via p21-activated kinase-1 signaling regulates heregulin-beta1-mediated angiogenesis. Journal of Biological Chemistry 275(50): 39451–39457, 2000Google Scholar
  35. 35.
    Kumar R, Yarmand-Bagheri R: The role of HER2 in angiogenesis. Seminars in Oncology 28(Suppl 16): 27–32, 2001Google Scholar
  36. 36.
    Pegram MD, Reese DM: Combined biological therapy of breast cancer using monoclonal antibodies directed against HER2/neu protein and vascular endothelial factor. Seminars in Oncology 29(3 Suppl 11): 29–37, 2002Google Scholar
  37. 37.
    Baker CH, Solorzano CC, Fidler IJ: Blockade of vascular endothelial growth factor receptor and epidermal growth factor receptor signaling for therapy of metastatic human pancreatic cancer. Cancer Res 62: 1996–2003, 2002Google Scholar
  38. 38.
    Santra M, Reed CC, Iozzo RV: Decorin binds to a narrow region of the epidermal growth factor (EGF) receptor, partially overlapping but distinct from the EGF-binding epitope. Journal of Biological Chemistry 277(38): 35671–35681, 2002Google Scholar
  39. 39.
    Cordero JB, Cozzolino M, Lu Y, Vidal M, Slatopolsky E, Stahl PD, Barbieri MA, Dusso A: 1,25-dihydroxyvitamin D down-regulates cell membrane growth-and nuclear growth-promoting signals by the epidermal growth factor receptor. Journal of Biological Chemistry 277(41): 38965–38971, 2002Google Scholar
  40. 40.
    Hung MC, Hortobagyi GN, Ueno NT: Development of clinical trial of E1A gene therapy targeting HER-2/neuoverexpressing breast and ovarian cancer. Advances in Experimental Medicine and Biology 465: 171–180, 2000Google Scholar
  41. 41.
    Scott GK, Marden C, Xu F, Kirk L, Benz CC: Transcriptional repression of ErbB2 by histone deacetylase inhibitors detected by a genomically integrated ErbB2 promoterreporting cell screen. Molecular Cancer Therapeutics 1(6): 385–392, 2002Google Scholar
  42. 42.
    Asada S, Choi Y, Yamada M, Wang SC, Hung MC, Qin J, Uesugi M: External control of Her2 expression and cancer cell growth by targeting a Ras-linked coactivator. Proceedings of the National Academy of Sciences of the United States of America 99(20): 12747–12752, 2002Google Scholar
  43. 43.
    Feng J, Adsay NV, Kruger M, Ellis KL, Nagothu K, Majumdar APN, Sarkar FH: Expression of ERRP in normal and neoplastic pancreata and its relationship to clinicopathologic parameters in pancreatic adenocarcinoma. Pancreas 25(4): 342–349, 2002Google Scholar
  44. 44.
    Kim S, Zagozdzon R, Meisler A, Baleja JD, Fu YG, Avraham S, Avraham H: Csk homologous kinase (CHK) and ErbB-2 interactions are directly coupled with CHK negative growth regulatory function in breast cancer. Journal of Biological Chemistry 277(39): 36465–36470, 2002Google Scholar
  45. 45.
    Xu WP, Marcu M, Yuan XT, Mimnaugh E, Patterson C, Neckers L: Chaperone-dependent E3 ubiquitin ligase CHIP mediates a degradative pathway for c-ErbB2 Neu. Proceedings of the National Academy of Sciences of the United States of America 99(20): 12847–12852, 2002Google Scholar
  46. 46.
    Katz M, Shtiegman K, Tal-Or P, Yakir L, Mosesson Y, Harari D, Machluf Y, Asao H, Jovin T, Sugamura K, Yarden Y: Ligand-independent degradation of epidermal growth factor receptor involves receptor ubiquitylation and hgs, an adaptor whose ubiquitin-interacting motif targets ubiquitylation by Nedd4. Traffic 3(10): 740–751, 2002Google Scholar

Copyright information

© Kluwer Academic Publishers 2003

Authors and Affiliations

  1. 1.Department of Molecular and Cellular OncologyThe University of Texas M. D. Anderson Cancer CenterHoustonUSA

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