Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

ERBB receptors and cancer: the complexity of targeted inhibitors

A Correction to this article was published on 01 July 2005

Key Points

  • The family of ERBB or epidermal growth factor (EGF) receptors includes four members: EGFR/ERBB1, ERBB2, ERBB3 and ERBB4. EGFR and ERBB2 are involved in development of numerous types of human cancer and they have been intensely pursued as therapeutic targets.

  • Two important types of ERBB inhibitor are in clinical use: humanized antibodies directed against the extracellular domain of EGFR or ERBB2, and small-molecule tyrosine-kinase inhibitors (TKIs) that compete with ATP in the tyrosine-kinase domain of the receptor.

  • In preclinical models, treatment of tumour cells with ERBB-directed TKIs and antibodies rapidly downregulates phosphatidylinositol-3-kinase–AKT, mitogen-activated protein kinase, SRC, and signal transducer and activator of transcription (STAT) signalling, and blocks the proliferation of tumour cells. In the clinic, skin biopsies (surrogate tissue), and to a limited extent tumours, have been analysed for the molecular consequences of treatment with ERBB inhibitors.

  • ERBB-directed therapeutics have demonstrated clinical efficacy; however, the antitumour effects are often not as strong as predicted from preclinical studies. There are likely to be various reasons why this is so, an important one being that other tumour-cell alterations influence the tumour response to ERBB-targeted inhibitors. Therefore, rational drug-combination strategies have great potential to combat the complexity of tumour biology.

Abstract

ERBB receptor tyrosine kinases have important roles in human cancer. In particular, the expression or activation of epidermal growth factor receptor and ERBB2 are altered in many epithelial tumours, and clinical studies indicate that they have important roles in tumour aetiology and progression. Accordingly, these receptors have been intensely studied to understand their importance in cancer biology and as therapeutic targets, and many ERBB inhibitors are now used in the clinic. We will discuss the significance of these receptors as clinical targets, in particular the molecular mechanisms underlying response.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: ERBB receptors, ligands, dimers and downstream signalling pathways.
Figure 2: Active ERBB receptors and downstream signalling pathways in a tumour setting.
Figure 3: ERBB-receptor ectodomain structures.
Figure 4: Mechanisms of resistance to anti-ERBB therapeutics.
Figure 5: Combination strategies to potentiate cellular response and overcome resistance.

References

  1. Riese, D. J. & Stern, D. F. Specificity within the EGF family/ErbB receptor family signaling network. Bioessays 20, 41–48 (1998).

    PubMed  Article  Google Scholar 

  2. Yarden, Y. & Sliwkowski, M. X. Untangling the ErbB signalling network. Nature Rev. Mol. Cell Biol. 2, 127–137 (2001).

    CAS  Article  Google Scholar 

  3. Olayioye, M. A., Neve, R. M., Lane, H. A. & Hynes, N. E. The ErbB signaling network: receptor heterodimerization in development and cancer. EMBO J. 19, 3159–3167 (2000).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  4. Schlessinger, J. Common and distinct elements in cellular signaling via EGF and FGF receptors. Science 306, 1506–1507 (2004).

    CAS  PubMed  Article  Google Scholar 

  5. Holbro, T. & Hynes, N. E. ErbB receptors: directing key signaling networks throughout life. Annu. Rev. Pharmacol. Toxicol. 44, 195–217 (2004).

    CAS  PubMed  Article  Google Scholar 

  6. Ramsauer, V. P., Carraway, C. A., Salas, P. J. & Carraway, K. L. Muc4/sialomucin complex, the intramembrane ErbB2 ligand, translocates ErbB2 to the apical surface in polarized epithelial cells. J. Biol. Chem. 278, 30142–30147 (2003).

    CAS  PubMed  Article  Google Scholar 

  7. Graus-Porta, D., Beerli, R. R., Daly, J. M. & Hynes, N. E. ErbB-2, the preferred heterodimerization partner of all ErbB receptors, is a mediator of lateral signaling. EMBO J. 16, 1647–1655 (1997).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  8. Yu, H. & Jove, R. The STATs of cancer — new molecular targets come of age. Nature Rev. Cancer 4, 97–105 (2004).

    CAS  Article  Google Scholar 

  9. Grandis, J. R. et al. Constitutive activation of Stat3 signaling abrogates apoptosis in squamous cell carcinogenesis in vivo. Proc. Natl Acad. Sci. USA 97, 4227–4232 (2000).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  10. Ishizawar, R. & Parsons, S. J. c-Src and cooperating partners in human cancer. Cancer Cell 6, 209–214 (2004).

    CAS  PubMed  Article  Google Scholar 

  11. Bjornsti, M. A. & Houghton, P. J. The TOR pathway: a target for cancer therapy. Nature Rev. Cancer 4, 335–348 (2004).

    CAS  Article  Google Scholar 

  12. Gschwind, A., Fischer, O. M. & Ullrich, A. The discovery of receptor tyrosine kinases: targets for cancer therapy. Nature Rev. Cancer 4, 361–370 (2004).

    CAS  Article  Google Scholar 

  13. Ohgaki, H. et al. Genetic pathways to glioblastoma: a population-based study. Cancer Res. 64, 6892–6899 (2004).

    CAS  PubMed  Article  Google Scholar 

  14. Sunpaweravong, P. et al. Epidermal growth factor receptor and cyclin D1 are independently amplified and overexpressed in esophageal squamous cell carcinoma. J. Cancer Res. Clin. Oncol. 131, 111–119 (2005).

    CAS  PubMed  Article  Google Scholar 

  15. Salomon, D. S., Brandt, R., Ciardiello, F. & Normanno, N. Epidermal growth factor-related peptides and their receptors in human malignancies. Crit. Rev. Oncol. Hematol. 19, 183–232 (1995).

    CAS  PubMed  Article  Google Scholar 

  16. Ekstrand, A. J., Sugawa, N., James, C. D. & Collins, V. P. Amplified and rearranged epidermal growth factor receptor genes in human glioblastomas reveal deletions of sequences encoding portions of the N- and/or C-terminal tails. Proc. Natl Acad. Sci. USA 89, 4309–4313 (1992).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  17. Moscatello, D. K. et al. Frequent expression of a mutant epidermal growth factor receptor in multiple human tumors. Cancer Res. 55, 5536–5539 (1995).

    CAS  PubMed  Google Scholar 

  18. Lynch, T. J. et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N. Engl. J. Med. 350, 2129–2139 (2004).

    CAS  PubMed  Article  Google Scholar 

  19. Paez, J. G. et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 304, 1497–1500 (2004).

    CAS  PubMed  Article  Google Scholar 

  20. Pao, W. et al. EGF receptor gene mutations are common in lung cancers from 'never smokers' and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc. Natl Acad. Sci. USA 101, 13306–13311 (2004). References 18–20 are the first reports to describe the presence of cancer-specific mutations in the EGFR kinase domain. Patients with non-small-cell lung tumours containing these mutations had a higher chance of responding to EGFR tyrosine-kinase inhibitors than patients expressing wild-type EGFR in their tumours.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  21. Slamon, D. J. et al. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 235, 177–182 (1987). This paper was the first to show that ERBB2 gene amplification is associated with an increased risk of relapse and death for patients with early-stage breast cancer.

    CAS  PubMed  Article  Google Scholar 

  22. Hynes, N. E. & Stern, D. F. The biology of erbB-2/neu/HER-2 and its role in cancer. Biochim. Biophys. Acta 1198, 165–184 (1994).

    PubMed  Google Scholar 

  23. Stephens, P. et al. Lung cancer: intragenic ERBB2 kinase mutations in tumours. Nature 431, 525–526 (2004).

    CAS  PubMed  Article  Google Scholar 

  24. Burgess, A. W. et al. An open-and-shut case? Recent insights into the activation of EGF/ErbB receptors. Mol. Cell 12, 541–552 (2003).

    CAS  PubMed  Article  Google Scholar 

  25. Garrett, T. P. et al. Crystal structure of a truncated epidermal growth factor receptor extracellular domain bound to transforming growth factor α. Cell 110, 763–773 (2002).

    CAS  PubMed  Article  Google Scholar 

  26. Ogiso, H. et al. Crystal structure of the complex of human epidermal growth factor and receptor extracellular domains. Cell 110, 775–787 (2002). References 25 and 26 are the first to show the crystal structure of the EGFR ectodomain in complex with a ligand. Although each ligand simultaneously contacts two binding sites in the ectodomain, the ligand does not span the ectodomain dimer; EGFR dimerization is entirely receptor mediated. In the latter publication, this unique receptor-mediated dimerization was verified by mutagenesis.

    CAS  PubMed  Article  Google Scholar 

  27. Cho, H. S. & Leahy, D. J. Structure of the extracellular region of HER3 reveals an interdomain tether. Science 297, 1330–1333 (2002).

    CAS  PubMed  Article  Google Scholar 

  28. Ferguson, K. M. et al. EGF activates its receptor by removing interactions that autoinhibit ectodomain dimerization. Mol. Cell 11, 507–517 (2003).

    CAS  PubMed  Article  Google Scholar 

  29. Batra, S. K. et al. Epidermal growth factor ligand-independent, unregulated, cell-transforming potential of a naturally occurring human mutant EGFRvIII gene. Cell Growth Differ. 6, 1251–1259 (1995).

    CAS  PubMed  Google Scholar 

  30. Garrett, T. P. et al. The crystal structure of a truncated ErbB2 ectodomain reveals an active conformation, poised to interact with other ErbB receptors. Mol. Cell 11, 495–505 (2003).

    CAS  PubMed  Article  Google Scholar 

  31. Cho, H. S. et al. Structure of the extracellular region of HER2 alone and in complex with the Herceptin Fab. Nature 421, 756–760 (2003).

    CAS  PubMed  Article  Google Scholar 

  32. Harris, R. C., Chung, E. & Coffey, R. J. EGF receptor ligands. Exp. Cell Res. 284, 2–13 (2003).

    CAS  PubMed  Article  Google Scholar 

  33. Falls, D. L. Neuregulins: functions, forms, and signaling strategies. Exp. Cell Res. 284, 14–30 (2003).

    CAS  PubMed  Article  Google Scholar 

  34. Borrell-Pages, M., Rojo, F., Albanell, J., Baselga, J. & Arribas, J. TACE is required for the activation of the EGFR by TGF-α in tumors. EMBO J. 22, 1114–1124 (2003).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  35. Daub, H., Weiss, F. U., Wallasch, C. & Ullrich, A. Role of transactivation of the EGF receptor in signalling by G-protein-coupled receptors. Nature 379, 557–560 (1996). Treatment of cells with GPCR agonists induces rapid EGFR tyrosine phosphorylation. This has been termed EGFR transactivation and was shown in this paper to result from metalloproteinase activation leading to the cleavage and release of HB-EGF.

    CAS  Article  PubMed  Google Scholar 

  36. Prenzel, N. et al. EGF receptor transactivation by G-protein-coupled receptors requires metalloproteinase cleavage of proHB-EGF. Nature 402, 884–888 (1999).

    CAS  PubMed  Article  Google Scholar 

  37. Luttrell, L. M., Daaka, Y. & Lefkowitz, R. J. Regulation of tyrosine kinase cascades by G-protein-coupled receptors. Curr. Opin. Cell Biol. 11, 177–183 (1999).

    CAS  Article  PubMed  Google Scholar 

  38. Izumi, Y. et al. A metalloprotease-disintegrin, MDC9/meltrin-γ/ADAM9 and PKCδ are involved in TPA-induced ectodomain shedding of membrane-anchored heparin-binding EGF-like growth factor. EMBO J. 17, 7260–7272 (1998).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  39. Gschwind, A., Hart, S., Fischer, O. M. & Ullrich, A. TACE cleavage of proamphiregulin regulates GPCR-induced proliferation and motility of cancer cells. EMBO J. 22, 2411–2421 (2003).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  40. Wakatsuki, S., Kurisaki, T. & Sehara-Fujisawa, A. Lipid rafts identified as locations of ectodomain shedding mediated by Meltrin β/ADAM19. J. Neurochem. 89, 119–123 (2004).

    CAS  PubMed  Article  Google Scholar 

  41. Daaka, Y. G proteins in cancer: the prostate cancer paradigm. Sci. STKE 216, re2 (2004).

    Google Scholar 

  42. Scher, H. I. et al. Changing pattern of expression of the epidermal growth factor receptor and transforming growth factor α in the progression of prostatic neoplasms. Clin. Cancer Res. 1, 545–550 (1995).

    CAS  PubMed  Google Scholar 

  43. Civenni, G., Holbro, T. & Hynes, N. E. Wnt1 and Wnt5a induce cyclin D1 expression through ErbB1 transactivation in HC11 mammary epithelial cells. EMBO Rep. 4, 166–171 (2003).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  44. Razandi, M., Pedram, A., Park, S. T. & Levin, E. R. Proximal events in signaling by plasma membrane estrogen receptors. J. Biol. Chem. 278, 2701–2712 (2003).

    CAS  PubMed  Article  Google Scholar 

  45. Shou, J. et al. Mechanisms of tamoxifen resistance: increased estrogen receptor-HER2/neu cross-talk in ER/HER2-positive breast cancer. J. Natl Cancer Inst. 96, 926–935 (2004).

    CAS  PubMed  Article  Google Scholar 

  46. Luttrell, D. K. & Luttrell, L. M. Not so strange bedfellows: G-protein-coupled receptors and Src family kinases. Oncogene 23, 7969–7978 (2004).

    CAS  PubMed  Article  Google Scholar 

  47. Poghosyan, Z. et al. Phosphorylation-dependent interactions between ADAM15 cytoplasmic domain and Src family protein-tyrosine kinases. J. Biol. Chem. 277, 4999–5007 (2002).

    CAS  PubMed  Article  Google Scholar 

  48. Seals, D. F. & Courtneidge, S. A. The ADAMs family of metalloproteases: multidomain proteins with multiple functions. Genes Dev. 17, 7–30 (2003).

    CAS  PubMed  Article  Google Scholar 

  49. Bolen, J. B., Veillette, A., Schwartz, A. M., DeSeau, V. & Rosen, N. Activation of pp60c-src protein kinase activity in human colon carcinoma. Proc. Natl Acad. Sci. USA 84, 2251–2255 (1987).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  50. Ottenhoff-Kalff, A. E. et al. Characterization of protein tyrosine kinases from human breast cancer: involvement of the c-src oncogene product. Cancer Res. 52, 4773–4778 (1992).

    CAS  PubMed  Google Scholar 

  51. Sliwkowski, M. X. et al. Nonclinical studies addressing the mechanism of action of trastuzumab (Herceptin). Semin. Oncol. 26, 60–70 (1999). The different mechanisms that have been proposed to contribute to trastuzumab's clinical efficacy are discussed in this paper.

    CAS  PubMed  Google Scholar 

  52. Petit, A. M. et al. Neutralizing antibodies against epidermal growth factor and ErbB-2/neu receptor tyrosine kinases down-regulate vascular endothelial growth factor production by tumor cells in vitro and in vivo: angiogenic implications for signal transduction therapy of solid tumors. Am. J. Pathol. 151, 1523–1530 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Overholser, J. P., Prewett, M. C., Hooper, A. T., Waksal, H. W. & Hicklin, D. J. Epidermal growth factor receptor blockade by antibody IMC-C225 inhibits growth of a human pancreatic carcinoma xenograft in nude mice. Cancer 89, 74–82 (2000).

    CAS  PubMed  Article  Google Scholar 

  54. Lane, H. A. et al. ErbB2 potentiates breast tumor proliferation through modulation of p27Kip1–Cdk2 complex formation: receptor overexpression does not determine growth dependency. Mol. Cell. Biol. 20, 3210–3223 (2000).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  55. Motoyama, A. B., Hynes, N. E. & Lane, H. A. The efficacy of ErbB receptor-targeted anticancer therapeutics is influenced by the availability of epidermal growth factor-related peptides. Cancer Res. 62, 3151–3158 (2002). Trastuzumab-treated breast cancer cells escape from the antiproliferative effects of the monoclonal antibody in the presence of ERBB ligands owing to the fact that trastuzumab cannot block the homo/heterodimerization of other ERBB receptors.

    CAS  PubMed  Google Scholar 

  56. Nagata, Y. et al. PTEN activation contributes to tumor inhibition by trastuzumab, and loss of PTEN predicts trastuzumab resistance in patients. Cancer Cell 6, 117–127 (2004).

    CAS  PubMed  Article  Google Scholar 

  57. Kerbel, R. & Folkman, J. Clinical translation of angiogenesis inhibitors. Nature Rev. Cancer 2, 727–739 (2002).

    CAS  Article  Google Scholar 

  58. Baselga, J. et al. 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. J. Clin. Oncol. 20, 4292–4302 (2002).

    CAS  Article  PubMed  Google Scholar 

  59. Albanell, J. et al. Pharmacodynamic studies of the epidermal growth factor receptor inhibitor ZD1839 in skin from cancer patients: histopathologic and molecular consequences of receptor inhibition. J. Clin. Oncol. 20, 110–124 (2002).

    CAS  Article  PubMed  Google Scholar 

  60. Malik, S. N. et al. Pharmacodynamic evaluation of the epidermal growth factor receptor inhibitor OSI-774 in human epidermis of cancer patients. Clin. Cancer Res. 9, 2478–2486 (2003).

    CAS  PubMed  Google Scholar 

  61. Vanhoefer, U. et al. Phase I study of the humanized antiepidermal growth factor receptor monoclonal antibody EMD72000 in patients with advanced solid tumors that express the epidermal growth factor receptor. J. Clin. Oncol. 22, 175–184 (2004).

    CAS  PubMed  Article  Google Scholar 

  62. Baselga, J. Skin as a surrogate tissue for pharmacodynamic end points: is it deep enough? Clin. Cancer Res. 9, 2389–2390 (2003).

    PubMed  Google Scholar 

  63. Daneshmand, M. et al. A pharmacodynamic study of the epidermal growth factor receptor tyrosine kinase inhibitor ZD1839 in metastatic colorectal cancer patients. Clin. Cancer Res. 9, 2457–2464 (2003).

    CAS  PubMed  Google Scholar 

  64. Tabernero, J. et al. A phase I pharmacokinetic (PK) and serial tumor and skin pharmacodynamic (PD) study of weekly, every 2 weeks or every 3 weeks 1-hour (h) infusion EMD72000, an humanized monoclonal anti-epidermal growth factor receptor (EGFR) antibody, in patients (p) with advanced tumors known to overexpress the EGFR. Eur. J. Cancer 38 (Suppl. 7), 69 (2002).

    Google Scholar 

  65. Clynes, R. A., Towers, T. L., Presta, L. G. & Ravetch, J. V. Inhibitory Fc receptors modulate in vivo cytoxicity against tumor targets. Nature Med. 6, 443–446 (2000).

    CAS  PubMed  Article  Google Scholar 

  66. Herbst, R. S., Fukuoka, M. & Baselga, J. Timeline: Gefitinib- a novel targeted approach to treating cancer. Nature Rev. Cancer 4, 956–965 (2004).

    CAS  Article  Google Scholar 

  67. Sordella, R., Bell, D. W., Haber, D. A. & Settleman, J. Gefitinib-sensitizing EGFR mutations in lung cancer activate anti-apoptotic pathways. Science 305, 1163–1167 (2004).

    CAS  PubMed  Article  Google Scholar 

  68. Hudziak, R. M. et al. p185HER2 monoclonal antibody has antiproliferative effects in vitro and sensitizes human breast tumor cells to tumor necrosis factor. Mol. Cell. Biol. 9, 1165–1172 (1989).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Cobleigh, M. A. et al. Multinational study of the efficacy and safety of humanized anti-HER2 monoclonal antibody in women who have HER2-overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease. J. Clin. Oncol. 17, 2639–2648 (1999).

    CAS  PubMed  Article  Google Scholar 

  70. Molina, M. A. et al. Trastuzumab (herceptin), a humanized anti-Her2 receptor monoclonal antibody, inhibits basal and activated Her2 ectodomain cleavage in breast cancer cells. Cancer Res. 61, 4744–4749 (2001).

    CAS  PubMed  Google Scholar 

  71. Hanahan, D. & Weinberg, R. A. The hallmarks of cancer. Cell 100, 57–70 (2000).

    CAS  Article  PubMed  Google Scholar 

  72. Vogel, C. L. et al. Efficacy and safety of trastuzumab as a single agent in first-line treatment of HER2-overexpressing metastatic breast cancer. J. Clin. Oncol. 20, 719–726 (2002).

    CAS  PubMed  Article  Google Scholar 

  73. Pao, W. et al. Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. PLoS Med. 2, 1–11 (2005). This paper describes the identification of acquired mutations in the EGFR kinase domain of cancer patients who have become resistant to gefitinib or erlotinib.

    Article  CAS  Google Scholar 

  74. Gorre, M. E. et al. Clinical resistance to STI-571 cancer therapy caused by BCRABL gene mutation or amplification. Science 293, 876–880 (2001).

    CAS  PubMed  Article  Google Scholar 

  75. Harries, M. & Smith, I. The development and clinical use of trastuzumab (Herceptin). Endocr. Relat. Cancer 9, 75–85 (2002).

    CAS  PubMed  Article  Google Scholar 

  76. Agus, D. B. et al. Targeting ligand-activated ErbB2 signaling inhibits breast and prostate tumor growth. Cancer Cell 2, 127–137 (2002).

    CAS  PubMed  Article  Google Scholar 

  77. Franklin, M. C. et al. Insights into ErbB signaling from the structure of the ErbB2-pertuzumab complex. Cancer Cell 5, 317–328 (2004).

    CAS  PubMed  Article  Google Scholar 

  78. Jackson, J. G., St Clair, P., Sliwkowski, M. X. & Brattain, M. G. Blockade of epidermal growth factor- or heregulin-dependent ErbB2 activation with the anti-ErbB2 monoclonal antibody 2C4 has divergent downstream signaling and growth effects. Cancer Res. 64, 2601–2609 (2004).

    CAS  PubMed  Article  Google Scholar 

  79. Rubin Grandis, J. et al. Levels of TGF-α and EGFR protein in head and neck squamous cell carcinoma and patient survival. J. Natl Cancer Inst. 90, 824–832 (1998).

    CAS  PubMed  Article  Google Scholar 

  80. Laban, C., Bustin, S. A. & Jenkins, P. J. The GH-IGF-I axis and breast cancer. Trends Endocrinol Metab. 14, 28–34 (2003).

    CAS  PubMed  Article  Google Scholar 

  81. Adnane, J. et al. BEK and FLG, two receptors to members of the FGF family, are amplified in subsets of human breast cancers. Oncogene 6, 659–663 (1991).

    CAS  PubMed  Google Scholar 

  82. 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. 93, 1852–1857 (2001). Results in this paper show that activation of the IGF1R in ERBB2-overexpressing breast cancer cells renders initially trastuzumab-sensitive cells resistant to the antibody.

    CAS  PubMed  Article  Google Scholar 

  83. Lu, Y., Zi, X. & Pollak, M. Molecular mechanisms underlying IGF-I-induced attenuation of the growth-inhibitory activity of trastuzumab (Herceptin) on SKBR3 breast cancer cells. Int. J. Cancer 108, 334–341 (2004).

    CAS  PubMed  Article  Google Scholar 

  84. Nahta, R., Takahashi, T., Ueno, N. T., Hung, M. C. & Esteva, F. J. P27kip1 down-regulation is associated with trastuzumab resistance in breast cancer cells. Cancer Res. 64, 3981–3986 (2004).

    CAS  PubMed  Article  Google Scholar 

  85. Camirand, A., Lu, Y. & Pollak, M. Co-targeting HER2/ErbB2 and insulin-like growth factor-1 receptors causes synergistic inhibition of growth in HER2-overexpressing breast cancer cells. Med. Sci. Monit. 8, BR521–BR526 (2002).

    CAS  PubMed  Google Scholar 

  86. Janmaat, M. L., Kruyt, F. A., Rodriguez, J. A. & Giaccone, G. Response to epidermal growth factor receptor inhibitors in non-small cell lung cancer cells: limited antiproliferative effects and absence of apoptosis associated with persistent activity of extracellular signal-regulated kinase or Akt kinase pathways. Clin. Cancer Res. 9, 2316–2326 (2003).

    CAS  PubMed  Google Scholar 

  87. She, Q. B., Solit, D., Basso, A. & Moasser, M. M. Resistance to gefitinib in PTEN-null HER-overexpressing tumor cells can be overcome through restoration of PTEN function or pharmacologic modulation of constitutive phosphatidylinositol 3'-kinase/Akt pathway signaling. Clin. Cancer Res. 9, 4340–4346 (2003).

    CAS  PubMed  Google Scholar 

  88. Bianco, R. et al. Loss of PTEN/MMAC1/TEP in EGF receptor-expressing tumor cells counteracts the antitumor action of EGFR tyrosine kinase inhibitors. Oncogene 22, 2812–2822 (2003). This paper shows that tumour cells with low PTEN levels are resistance to ERBB-targeted inhibitors.

    CAS  PubMed  Article  Google Scholar 

  89. Eng, C. PTEN: one gene, many syndromes. Hum. Mutat. 22, 183–198 (2003).

    CAS  PubMed  Article  Google Scholar 

  90. Thompson, J. E. & Thompson, C. B. Putting the rap on Akt. J. Clin. Oncol. 22, 4217–4226 (2004).

    CAS  PubMed  Article  Google Scholar 

  91. Samuels, Y. et al. High frequency of mutations of the PIK3CA gene in human cancers. Science 304, 554 (2004).

    CAS  PubMed  Article  Google Scholar 

  92. Krymskaya, V. P. Tumour suppressors hamartin and tuberin: intracellular signalling. Cell Signal. 15, 729–739 (2003).

    CAS  PubMed  Article  Google Scholar 

  93. Dutcher, J. P. Mammalian target of rapamycin (mTOR) inhibitors. Curr. Oncol. Rep. 6, 111–115 (2004).

    PubMed  Article  Google Scholar 

  94. Koziczak, M. & Hynes, N. E. Cooperation between fibroblast growth factor receptor-4 and ErbB2 in regulation of cyclin D1 translation. J. Biol. Chem. 279, 50004–50011 (2004).

    CAS  PubMed  Article  Google Scholar 

  95. Zhou, X. et al. Activation of the Akt/mammalian target of rapamycin/4E-BP1 pathway by ErbB2 overexpression predicts tumor progression in breast cancers. Clin. Cancer Res. 10, 6779–6788 (2004).

    CAS  PubMed  Article  Google Scholar 

  96. Aoki, M., Blazek, E. & Vogt, P. K. A role of the kinase mTOR in cellular transformation induced by the oncoproteins P3k and Akt. Proc. Natl Acad. Sci. USA 98, 136–1341 (2001). Results presented in this paper justify combining mTOR inhibitors with inhibitors blocking other signalling entities such as the ERBB receptors, as the data demonstrate that cellular transformation can be independently driven by non-overlapping signalling pathways.

    CAS  PubMed  Article  Google Scholar 

  97. Venkateswarlu, S. et al. Autocrine heregulin generates growth factor independence and blocks apoptosis in colon cancer cells. Oncogene 21, 78–86 (2002).

    CAS  PubMed  Article  Google Scholar 

  98. Stal, O. et al. Akt kinases in breast cancer and the results of adjuvant therapy. Breast Cancer Res. 5, R37–R44 (2003).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  99. Clark, A. S., West, K., Streicher, S. & Dennis, P. A. Constitutive and inducible Akt activity promotes resistance to chemotherapy, trastuzumab, or tamoxifen in breast cancer cells. Mol. Cancer Ther. 1, 707–717 (2002).

    CAS  PubMed  Google Scholar 

  100. Majumder, P. K. et al. mTOR inhibition reverses Akt-dependent prostate intraepithelial neoplasia through regulation of apoptotic and HIF-1-dependent pathways. Nature Med. 10, 594–601 (2004).

    CAS  PubMed  Article  Google Scholar 

  101. Neshat, M. S. et al. Enhanced sensitivity of PTEN-deficient tumors to inhibition of FRAP/mTOR. Proc. Natl Acad. Sci. USA 98, 10314–10319 (2001). This paper shows that PTEN-deficient tumour cells are particularly sensitive to mTOR inhibition. These results are important because they indicate that activation of the PI3K pathway could affect response to mTOR inhibition.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  102. Doisneau-Sixou, S. F. et al. Estrogen and antiestrogen regulation of cell cycle progression in breast cancer cells. Endocr. Relat. Cancer 10, 179–186 (2003).

    CAS  PubMed  Article  Google Scholar 

  103. Systemic treatment of early breast cancer by hormonal, cytotoxic, or immune therapy. 133 randomised trials involving 31,000 recurrences and 24,000 deaths among 75,000 women. Early Breast Cancer Trialists' Collaborative Group. Lancet 339, 1–15 (1992).

  104. Robertson, J. F. Selective oestrogen receptor modulators/new antioestrogens: a clinical perspective. Cancer Treat. Rev. 30, 695–706 (2004).

    CAS  PubMed  Article  Google Scholar 

  105. Smith, I. E. & Dowsett, M. Aromatase inhibitors in breast cancer. N. Engl. J. Med. 348, 2431–2442 (2003).

    CAS  PubMed  Article  Google Scholar 

  106. Schiff, R. et al. Cross-talk between estrogen receptor and growth factor pathways as a molecular target for overcoming endocrine resistance. Clin. Cancer Res. 10, 331S–336S (2004).

    CAS  PubMed  Article  Google Scholar 

  107. Matsuda, S. et al. 17β-estradiol mimics ligand activity of the c-erbB2 protooncogene product. Proc. Natl Acad. Sci. USA 90, 10803–10807 (1993).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  108. Ellis, M. Overcoming endocrine therapy resistance by signal transduction inhibition. Oncologist 9 (Suppl. 3), 20–26 (2004).

    CAS  PubMed  Article  Google Scholar 

  109. Gee, J. M. et al. The antiepidermal growth factor receptor agent gefitinib (ZD1839/Iressa) improves antihormone response and prevents development of resistance in breast cancer in vitro. Endocrinology 144, 5105–5117 (2003).

    CAS  PubMed  Article  Google Scholar 

  110. Chung, Y. L., Sheu, M. L., Yang, S. C., Lin, C. H. & Yen, S. H. Resistance to tamoxifen-induced apoptosis is associated with direct interaction between Her2/neu and cell membrane estrogen receptor in breast cancer. Int. J. Cancer 97, 306–312 (2002).

    CAS  PubMed  Article  Google Scholar 

  111. Keshamouni, V. G., Mattingly, R. R. & Reddy, K. B. Mechanism of 17-β-estradiol-induced Erk1/2 activation in breast cancer cells. A role for HER2 AND PKC-δ. J. Biol. Chem. 277, 22558–22565 (2002).

    CAS  Article  PubMed  Google Scholar 

  112. Simoncini, T. et al. Interaction of oestrogen receptor with the regulatory subunit of phosphatidylinositol-3-OH kinase. Nature 407, 538–541 (2000).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  113. Ali, S. & Coombes, R. C. Endocrine-responsive breast cancer and strategies for combating resistance. Nature Rev. Cancer 2, 101–112 (2002).

    Article  Google Scholar 

  114. Martin, L. A. et al. Enhanced estrogen receptor (ER) α, ERBB2, and MAPK signal transduction pathways operate during the adaptation of MCF-7 cells to long term estrogen deprivation. J. Biol. Chem. 278, 30458–30468 (2003).

    CAS  PubMed  Article  Google Scholar 

  115. Dowsett, M. et al. HER-2 amplification impedes the antiproliferative effects of hormone therapy in estrogen receptor-positive primary breast cancer. Cancer Res. 61, 8452–8458 (2001).

    CAS  PubMed  Google Scholar 

  116. Dowsett, M. Molecular changes in tamoxifen-relapsed breast cancer: relationship between ER, HER2 and p38-MAP-kinase. Proc. Am. Soc. Clin. Oncol. 22, 3 (2003).

    Google Scholar 

  117. Arpino, G. et al. HER-2 amplification, HER-1 expression, and tamoxifen response in estrogen receptor-positive metastatic breast cancer: a southwest oncology group study. Clin. Cancer Res. 10, 5670–5676 (2004).

    CAS  PubMed  Article  Google Scholar 

  118. De Placido, S. et al. Twenty-year results of the Naples GUN randomized trial: predictive factors of adjuvant tamoxifen efficacy in early breast cancer. Clin. Cancer Res. 9, 1039–1046 (2003).

    CAS  PubMed  Google Scholar 

  119. Ellis, M. J. et al. Letrozole is more effective neoadjuvant endocrine therapy than tamoxifen for ErbB-1- and/or ErbB-2-positive, estrogen receptor-positive primary breast cancer: evidence from a phase III randomized trial. J. Clin. Oncol. 19, 3808–3816 (2001). This clinical study revealed that patients with EGFR- or ERBB2-positive breast tumours responded well to the aromatase inhibitor letrozole but poorly to the SERM tamoxifen. These results demonstrate the value of molecular profiling to aid the selection of appropriate targeted therapies.

    CAS  Article  PubMed  Google Scholar 

  120. Ropero, S. et al. Trastuzumab plus tamoxifen: anti-proliferative and molecular interactions in breast carcinoma. Breast Cancer Res. Treat. 86, 125–137 (2004).

    CAS  PubMed  Article  Google Scholar 

  121. Aboud-Pirak, E. et al. Efficacy of antibodies to epidermal growth factor receptor against KB carcinoma in vitro and in nude mice. J. Natl Cancer Inst. 80, 1605–1611 (1988).

    CAS  PubMed  Article  Google Scholar 

  122. Pietras, R. J. et al. Antibody to HER-2/neu receptor blocks DNA repair after cisplatin in human breast and ovarian cancer cells. Oncogene 9, 1829–1838 (1994). This paper provides a mechanism of the synergistic activity of trastuzumab and cisplatin in ERBB2-overexpressing cancer cells. Downregulation of ERBB2 signalling activity interferes with the ability of cancer cells to repair DNA adducts, leading to death of tumour cells.

    CAS  PubMed  Google Scholar 

  123. Pegram, M. D., Lopez, A., Konecny, G. & Slamon, D. J. Trastuzumab and chemotherapeutics: drug interactions and synergies. Semin. Oncol. 27, 21–25 (2000).

    CAS  PubMed  Google Scholar 

  124. Pegram, M. D. et al. Rational combinations of trastuzumab with chemotherapeutic drugs used in the treatment of breast cancer. J. Natl Cancer Inst. 96, 739–749 (2004).

    CAS  PubMed  Article  Google Scholar 

  125. Pegram, M. D. et al. Results of two open-label, multicenter phase II studies of docetaxel, platinum salts, and trastuzumab in HER2-positive advanced breast cancer. J. Natl Cancer Inst. 96, 759–769 (2004).

    CAS  PubMed  Article  Google Scholar 

  126. Ciardiello, F. et al. Antitumor effect and potentiation of cytotoxic drugs activity in human cancer cells by ZD-1839 (Iressa), an epidermal growth factor receptor-selective tyrosine kinase inhibitor. Clin. Cancer Res. 6, 2053–2063 (2000).

    CAS  PubMed  Google Scholar 

  127. Dancey, J. E. Predictive factors for epidermal growth factor receptor inhibitors — the bull's-eye hits the arrow. Cancer Cell 5, 411–415 (2004).

    CAS  PubMed  Article  Google Scholar 

  128. Holbro, T. et al. The ErbB2/ErbB3 heterodimer functions as an oncogenic unit: ErbB2 requires ErbB3 to drive breast tumor cell proliferation. Proc. Natl Acad. Sci. USA 100, 8933–8938 (2003). This paper uses elegant technology to demonstrate that ERBB2-overexpressing breast cancer cells use ERBB3 to activate the PI3K pathway. Both downregulation of ERBB3 expression and targeting ERBB2 directly with TKIs block proliferation of tumour cells.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  129. Mitsiades, C. S. et al. Inhibition of the insulin-like growth factor receptor-1 tyrosine kinase activity as a therapeutic strategy for multiple myeloma, other hematologic malignancies, and solid tumors. Cancer Cell 5, 221–230 (2004).

    CAS  PubMed  Article  Google Scholar 

  130. Ward, S. G. & Finan, P. Isoform-specific phosphoinositide 3-kinase inhibitors as therapeutic agents. Curr. Opin. Pharmacol. 3, 426–434 (2003).

    CAS  PubMed  Article  Google Scholar 

  131. Mills, G. B. et al. Linking molecular diagnostics to molecular therapeutics: targeting the PI3K pathway in breast cancer. Semin. Oncol. 30, 93–104 (2003).

    CAS  PubMed  Article  Google Scholar 

  132. Sebolt-Leopold, J. S. & Herrera, R. Targeting the mitogen-activated protein kinase cascade to treat cancer. Nature Rev. Cancer 4, 937–947 (2004).

    CAS  Article  Google Scholar 

  133. Dibb, N. J., Dilworth, S. M. & Mol, C. D. Switching on kinases: oncogenic activation of BRAF and the PDGFR family. Nature Rev. Cancer 4, 718–727 (2004).

    CAS  Article  Google Scholar 

  134. Wood, J. M. et al. PTK787/ZK 222584, a novel and potent inhibitor of vascular endothelial growth factor receptor tyrosine kinases, impairs vascular endothelial growth factor-induced responses and tumor growth after oral administration. Cancer Res. 60, 2178–2189 (2000).

    CAS  PubMed  Google Scholar 

  135. Shaheen, R. M. et al. Inhibited growth of colon cancer carcinomatosis by antibodies to vascular endothelial and epidermal growth factor receptors. Br. J. Cancer 85, 584–589 (2001).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  136. Traxler, P. et al. AEE788: a dual family epidermal growth factor receptor/ErbB2 and vascular endothelial growth factor receptor tyrosine kinase inhibitor with antitumor and antiangiogenic activity. Cancer Res. 64, 4931–4941 (2004). This paper presents an extensive in vitro and in vivo analysis of the activity of the multifunction inhibitor AEE788, which targets both ERBB and VEGFRs. A direct comparison with ERBB- and VEGFR-specific TKIs used in combination is performed.

    CAS  PubMed  Article  Google Scholar 

  137. Jorissen, R. N. et al. Epidermal growth factor receptor: mechanisms of activation and signalling. Exp. Cell Res. 284, 31–53 (2003).

    CAS  PubMed  Article  Google Scholar 

  138. Dankort, D., Jeyabalan, N., Jones, N., Dumont, D. J. & Muller, W. J. Multiple ErbB-2/Neu phosphorylation sites mediate transformation through distinct effector proteins. J. Biol. Chem. 276, 38921–38928 (2001).

    CAS  PubMed  Article  Google Scholar 

  139. Marone, R. et al. Memo mediates ErbB2-driven cell motility. Nature Cell Biol. 6, 515–522 (2004).

    CAS  PubMed  Article  Google Scholar 

  140. Kim, H. H., Vijapurkar, U., Hellyer, N. J., Bravo, D. & Koland, J. G. Signal transduction by epidermal growth factor and heregulin via the kinase-deficient ErbB3 protein. Biochem. J. 334 (Pt 1), 189–195 (1998).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  141. Yen, L. et al. Differential regulation of tumor angiogenesis by distinct ErbB homo- and heterodimers. Mol. Biol. Cell 13, 4029–4044 (2002).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  142. Baker, C. H. et al. Blockade of epidermal growth factor receptor signaling on tumor cells and tumor-associated endothelial cells for therapy of human carcinomas. Am. J. Pathol. 161, 929–938 (2002).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  143. Heimberger, A. B. et al. Brain tumors in mice are susceptible to blockade of epidermal growth factor receptor (EGFR) with the oral, specific, EGFR-tyrosine kinase inhibitor ZD1839 (iressa). Clin. Cancer Res. 8, 3496–3502 (2002).

    CAS  PubMed  Google Scholar 

  144. Shin, I. et al. PKB/Akt mediates cell-cycle progression by phosphorylation of p27Kip1 at threonine 157 and modulation of its cellular localization. Nature Med. 8, 1145–1152 (2002).

    CAS  PubMed  Article  Google Scholar 

  145. Miettinen, P. J. et al. Epithelial immaturity and multiorgan failure in mice lacking epidermal growth factor receptor. Nature 376, 337–341 (1995).

    CAS  PubMed  Article  Google Scholar 

  146. Sibilia, M. & Wagner, E. F. Strain-dependent epithelial defects in mice lacking the EGF receptor. Science 269, 234–238 (1995).

    CAS  PubMed  Article  Google Scholar 

  147. Threadgill, D. W. et al. Targeted disruption of mouse EGF receptor: effect of genetic background on mutant phenotype. Science 269, 230–234 (1995).

    CAS  PubMed  Article  Google Scholar 

  148. Tan, A. R. et al. Evaluation of biologic end points and pharmacokinetics in patients with metastatic breast cancer after treatment with erlotinib, an epidermal growth factor receptor tyrosine kinase inhibitor. J. Clin. Oncol. 22, 3080–3090 (2004).

    CAS  PubMed  Article  Google Scholar 

  149. Cohen, E. E. et al. Phase II trial of ZD1839 in recurrent or metastatic squamous cell carcinoma of the head and neck. J. Clin. Oncol. 21, 1980–1987 (2003).

    CAS  PubMed  Article  Google Scholar 

  150. Camus, P., Kudoh, S. & Ebina, M. Interstitial lung disease associated with drug therapy. Br. J. Cancer 91 (Suppl. 2), S18–S23 (2004).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  151. Sumpter, K., Harper-Wynne, C., O'Brien, M. & Congleton, J. Severe acute interstitial pnuemonia and gefitinib. Lung Cancer 43, 367–368 (2004).

    PubMed  Article  Google Scholar 

  152. Suzuki, H., Aoshiba, K., Yokohori, N. & Nagai, A. Epidermal growth factor receptor tyrosine kinase inhibition augments a murine model of pulmonary fibrosis. Cancer Res. 63, 5054–5059 (2003).

    CAS  PubMed  Google Scholar 

  153. Lee, K. F. et al. Requirement for neuregulin receptor erbB2 in neural and cardiac development. Nature 378, 394–398 (1995).

    CAS  PubMed  Article  Google Scholar 

  154. Crone, S. A. et al. ErbB2 is essential in the prevention of dilated cardiomyopathy. Nature Med. 8, 459–465 (2002).

    CAS  PubMed  Article  Google Scholar 

  155. Slamon, D. J. et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N. Engl. J. Med. 344, 783–792 (2001).

    CAS  Article  PubMed  Google Scholar 

  156. Gassmann, M. et al. Aberrant neural and cardiac development in mice lacking the ErbB4 neuregulin receptor. Nature 378, 390–394 (1995).

    CAS  PubMed  Article  Google Scholar 

  157. Meyer, D. & Birchmeier, C. Multiple essential functions of neuregulin in development. Nature 378, 386–390 (1995).

    CAS  PubMed  Article  Google Scholar 

  158. Fuchs, I. B. et al. Analysis of HER2 and HER4 in human myocardium to clarify the cardiotoxicity of trastuzumab (Herceptin). Breast Cancer Res. Treat. 82, 23–28 (2003).

    CAS  PubMed  Article  Google Scholar 

  159. Zhao, Y. Y. et al. Neuregulins promote survival and growth of cardiac myocytes. Persistence of ErbB2 and ErbB4 expression in neonatal and adult ventricular myocytes. J. Biol. Chem. 273, 10261–10269 (1998).

    CAS  PubMed  Article  Google Scholar 

  160. Sato, J. D. et al. Biological effects in vitro of monoclonal antibodies to human epidermal growth factor receptors. Mol. Biol. Med. 1, 511–529 (1983).

    CAS  PubMed  Google Scholar 

  161. Schreiber, A. B., Lax, I., Yarden, Y., Eshhar, Z. & Schlessinger, J. Monoclonal antibodies against receptor for epidermal growth factor induce early and delayed effects of epidermal growth factor. Proc. Natl Acad. Sci. USA 78, 7535–7539 (1981).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  162. Goldstein, N. I., Prewett, M., Zuklys, K., Rockwell, P. & Mendelsohn, J. Biological efficacy of a chimeric antibody to the epidermal growth factor receptor in a human tumor xenograft model. Clin. Cancer Res. 1, 1311–1318 (1995).

    CAS  PubMed  Google Scholar 

  163. Carter, P. et al. Humanization of an anti-p185HER2 antibody for human cancer therapy. Proc. Natl Acad. Sci. USA 89, 4285–4289 (1992).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  164. Honegger, A. M. et al. A mutant 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 (1987).

    CAS  PubMed  PubMed Central  Google Scholar 

  165. Traxler, P. Tyrosine kinases as targets in cancer therapy- successes and failures. Expert Opin. Ther. Targets 7, 215–234 (2003).

    CAS  PubMed  Article  Google Scholar 

  166. Gazit, A., Yaish, P., Gilon, C. & Levitzki, A. Tyrphostins I: synthesis and biological activity of protein tyrosine kinase inhibitors. J. Med. Chem. 32, 2344–2352 (1989).

    CAS  PubMed  Article  Google Scholar 

Download references

Acknowledgements

We would like to thank A. Badache and T. Schlange for critically reviewing the manuscript. The laboratory of N.E.H. is supported by the Novartis Research Foundation and grants from the Swiss Cancer League and the European Union.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Nancy E. Hynes.

Ethics declarations

Competing interests

During the preparation of this review, Heidi A. Lane was employed by Novartis; Nancy E. Hynes was a Novartis consultant.

Related links

Related links

DATABASES

Entrez Gene

ADAM10

ADAM15

ADAM17

ADAM9

amphiregulin

betacellulin

EGF

EGFR/ERBB1

epiregulin

ERBB2

ERBB3

ERBB4

HB-EGF

IGF1R

MMP2

MMP9

mTOR

MUC4

NRG1

NRG2

NRG3

NRG4

p27

SRC

transforming growth factor-α

Glossary

G-PROTEIN-COUPLED RECEPTORS

A large family of receptors that span the membrane seven times and couple to G proteins, which are composed of α-, β- and γ-subunits. The α-subunit contains the nucleotide (GTP or GDP) binding site, and the β- and γ-subunits behave as a single entity.

XENOGRAFT

Commonly refers to the growth of tumour cells as tumours in immunocomprised mice.

SURROGATE TISSUE

To examine the in vivo efficacy of tyrosine-kinase inhibitors targeted at epidermal growth factor receptor (EGFR) in cancer patients, skin biopsies of treated patients have been examined for downregulation of EGFR phosphorylation.

AUTOCRINE

A form of bioregulation in which a secreted peptide affects only the cell from which it is secreted.

PARACRINE

A form of bioregulation in which a secreted peptide affects a neighbouring cell.

NEOADJUVANT

A therapy that is given before the main treatment, which could be, for example, surgery.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Hynes, N., Lane, H. ERBB receptors and cancer: the complexity of targeted inhibitors. Nat Rev Cancer 5, 341–354 (2005). https://doi.org/10.1038/nrc1609

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrc1609

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing