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Status of Epidermal Growth Factor Receptor Antagonists in the Biology and Treatment of Cancer

John Mendelsohn, Jose Baselga

From the University of Texas M.D. Anderson Cancer Center, Houston, TX; and Vall d’Hebron University Hospital, Universidad Autonoma, Barcelona, Spain.

Address reprint requests to John Mendelsohn, MD, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX, 77030-4009; email: jmendelsohn{at}mdanderson.org.

The epidermal growth factor receptor (EGFR) is a tyrosine kinase receptor of the ErbB family that is abnormally activated in many epithelial tumors. Receptor activation leads to recruitment and phosphorylation of several downstream intracellular substrates, leading to mitogenic signaling and other tumor-promoting cellular activities. In human tumors, receptor overexpression correlates with a more aggressive clinical course. Taken together, these observations indicate that the EGFR is a promising target for cancer therapy. Monoclonal antibodies directed at the ligand-binding extracellular domain and low–molecular weight inhibitors of the receptor’s tyrosine kinase are currently in advanced stages of clinical development. These agents prevent ligand-induced receptor activation and downstream signaling, which results in cell cycle arrest, promotion of apoptosis, and inhibition of angiogenesis. They also enhance the antitumor effects of chemotherapy and radiation therapy. In patients, anti-EGFR agents can be given safely at doses that fully inhibit receptor signaling, and single-agent activity has been observed against a variety of tumor types, including colon carcinoma, non–small-cell lung cancer, head and neck cancer, ovarian carcinoma, and renal cell carcinoma. Although antitumor activity is significant, responses have been seen in only a minority of the patients treated. In some clinical trials, anti-EGFR agents enhanced the effects of conventional chemotherapy and radiation therapy. Ongoing research efforts are directed at the selection of patients with EGFR-dependent tumors, identification of the differences among the various classes of agents, and new clinical development strategies.

Supported in part by the Spanish Health Ministry grant "Fondo de Investigación Sanitaria" (01/0040–02; J.B).

J.M. is on the Board of Directors of ImClone Systems Inc (New York, NY) and holds stock options.

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				A. B. Riemer, H. Kurz, M. Klinger, O. Scheiner, C. C. Zielinski, and E. Jensen-Jarolim Vaccination With Cetuximab Mimotopes and Biological Properties of Induced Anti-Epidermal Growth Factor Receptor Antibodies J Natl Cancer Inst, November 16, 2005; 97(22): 1663 - 1670. [Abstract] [Full Text] [PDF]

				M. Ates, O. Altundag, S. Aktolga, and K. Altundag Association between cyclooxygenase and epidermal growth factor receptor pathways in non-small cell lung cancer J. Thorac. Cardiovasc. Surg., November 1, 2005; 130(5): 1484 - 1485. [Full Text] [PDF]

				L. R. Perk, G. W.M. Visser, M. J.W.D. Vosjan, M. Stigter-van Walsum, B. M. Tijink, C. R. Leemans, and G. A.M.S. van Dongen 89Zr as a PET Surrogate Radioisotope for Scouting Biodistribution of the Therapeutic Radiometals 90Y and 177Lu in Tumor-Bearing Nude Mice After Coupling to the Internalizing Antibody Cetuximab J. Nucl. Med., November 1, 2005; 46(11): 1898 - 1906. [Abstract] [Full Text] [PDF]

				S. Van Schaeybroeck, A. Karaiskou-McCaul, D. Kelly, D. Longley, L. Galligan, E. Van Cutsem, and P. Johnston Epidermal Growth Factor Receptor Activity Determines Response of Colorectal Cancer Cells to Gefitinib Alone and in Combination with Chemotherapy Clin. Cancer Res., October 15, 2005; 11(20): 7480 - 7489. [Abstract] [Full Text] [PDF]

				F. T. Lee, A. J. Mountain, M. P. Kelly, C. Hall, A. Rigopoulos, T. G. Johns, F. E. Smyth, M. W. Brechbiel, E. C. Nice, A. W. Burgess, et al. Enhanced Efficacy of Radioimmunotherapy with 90Y-CHX-A''-DTPA-hu3S193 by Inhibition of Epidermal Growth Factor Receptor (EGFR) Signaling with EGFR Tyrosine Kinase Inhibitor AG1478 Clin. Cancer Res., October 1, 2005; 11(19): 7080s - 7086s. [Abstract] [Full Text] [PDF]

				K. Dittmann, C. Mayer, B. Fehrenbacher, M. Schaller, U. Raju, L. Milas, D. J. Chen, R. Kehlbach, and H. P. Rodemann Radiation-induced Epidermal Growth Factor Receptor Nuclear Import Is Linked to Activation of DNA-dependent Protein Kinase J. Biol. Chem., September 2, 2005; 280(35): 31182 - 31189. [Abstract] [Full Text] [PDF]

				S. M. Bentzen, B. M. Atasoy, F. M. Daley, S. Dische, P. I. Richman, M. I. Saunders, K. R. Trott, and G. D. Wilson Epidermal Growth Factor Receptor Expression in Pretreatment Biopsies From Head and Neck Squamous Cell Carcinoma As a Predictive Factor for a Benefit From Accelerated Radiation Therapy in a Randomized Controlled Trial J. Clin. Oncol., August 20, 2005; 23(24): 5560 - 5567. [Abstract] [Full Text] [PDF]

				J. Baselga, J. M. Trigo, J. Bourhis, J. Tortochaux, H. Cortes-Funes, R. Hitt, P. Gascon, N. Amellal, A. Harstrick, and A. Eckardt Phase II Multicenter Study of the Antiepidermal Growth Factor Receptor Monoclonal Antibody Cetuximab in Combination With Platinum-Based Chemotherapy in Patients With Platinum-Refractory Metastatic and/or Recurrent Squamous Cell Carcinoma of the Head and Neck J. Clin. Oncol., August 20, 2005; 23(24): 5568 - 5577. [Abstract] [Full Text] [PDF]

				D. Schrag, K. Y. Chung, C. Flombaum, and L. Saltz Cetuximab Therapy and Symptomatic Hypomagnesemia J Natl Cancer Inst, August 17, 2005; 97(16): 1221 - 1224. [Abstract] [Full Text] [PDF]

				C. Montagut, J. J. Grau, R. Grimalt, J. Codony, J. Ferrando, and J. Albanell Abnormal Hair Growth in a Patient With Head and Neck Cancer Treated With the Anti-Epidermal Growth Factor Receptor Monoclonal Antibody Cetuximab J. Clin. Oncol., August 1, 2005; 23(22): 5273 - 5275. [Full Text] [PDF]

				L. Yuste, J. C. Montero, A. Esparis-Ogando, and A. Pandiella Activation of ErbB2 by Overexpression or by Transmembrane Neuregulin Results in Differential Signaling and Sensitivity to Herceptin Cancer Res., August 1, 2005; 65(15): 6801 - 6810. [Abstract] [Full Text] [PDF]

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				Y. Zhou and M. G. Brattain Synergy of Epidermal Growth Factor Receptor Kinase Inhibitor AG1478 and ErbB2 Kinase Inhibitor AG879 in Human Colon Carcinoma Cells Is Associated with Induction of Apoptosis Cancer Res., July 1, 2005; 65(13): 5848 - 5856. [Abstract] [Full Text] [PDF]

				D. A. Haas-Kogan, M. D. Prados, T. Tihan, D. A. Eberhard, N. Jelluma, N. D. Arvold, R. Baumber, K. R. Lamborn, A. Kapadia, M. Malec, et al. Epidermal Growth Factor Receptor, Protein Kinase B/Akt, and Glioma Response to Erlotinib J Natl Cancer Inst, June 15, 2005; 97(12): 880 - 887. [Abstract] [Full Text] [PDF]

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				D. Lu, H. Zhang, H. Koo, J. Tonra, P. Balderes, M. Prewett, E. Corcoran, V. Mangalampalli, R. Bassi, D. Anselma, et al. A Fully Human Recombinant IgG-like Bispecific Antibody to Both the Epidermal Growth Factor Receptor and the Insulin-like Growth Factor Receptor for Enhanced Antitumor Activity J. Biol. Chem., May 20, 2005; 280(20): 19665 - 19672. [Abstract] [Full Text] [PDF]

				G. Giaccone Epidermal Growth Factor Receptor Inhibitors in the Treatment of Non-Small-Cell Lung Cancer J. Clin. Oncol., May 10, 2005; 23(14): 3235 - 3242. [Abstract] [Full Text] [PDF]

				D. H. Lee, J.-Y. Han, H. G. Lee, J. J. Lee, E. K. Lee, H. Y. Kim, H. K. Kim, E. K. Hong, and J. S. Lee Gefitinib as a First-Line Therapy of Advanced or Metastatic Adenocarcinoma of the Lung in Never-Smokers Clin. Cancer Res., April 15, 2005; 11(8): 3032 - 3037. [Abstract] [Full Text] [PDF]

				S.-W. Han, T.-Y. Kim, P. G. Hwang, S. Jeong, J. Kim, I. S. Choi, D.-Y. Oh, J. H. Kim, D.-W. Kim, D. H. Chung, et al. Predictive and Prognostic Impact of Epidermal Growth Factor Receptor Mutation in Non-Small-Cell Lung Cancer Patients Treated With Gefitinib J. Clin. Oncol., April 10, 2005; 23(11): 2493 - 2501. [Abstract] [Full Text] [PDF]

				J. Baselga and C. L. Arteaga Critical Update and Emerging Trends in Epidermal Growth Factor Receptor Targeting in Cancer J. Clin. Oncol., April 10, 2005; 23(11): 2445 - 2459. [Abstract] [Full Text] [PDF]

				W. Pao and V. A. Miller Epidermal Growth Factor Receptor Mutations, Small-Molecule Kinase Inhibitors, and Non-Small-Cell Lung Cancer: Current Knowledge and Future Directions J. Clin. Oncol., April 10, 2005; 23(11): 2556 - 2568. [Abstract] [Full Text] [PDF]

				M. R. Raspollini, F. Castiglione, F. Garbini, A. Villanucci, G. Amunni, G. Baroni, V. Boddi, and G. L. Taddei Correlation of Epidermal Growth Factor Receptor Expression with Tumor Microdensity Vessels and with Vascular Endothelial Growth Factor Expression in Ovarian Carcinoma International Journal of Surgical Pathology, April 1, 2005; 13(2): 135 - 142. [Abstract] [PDF]

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				A. Thelemann, F. Petti, G. Griffin, K. Iwata, T. Hunt, T. Settinari, D. Fenyo, N. Gibson, and J. D. Haley Phosphotyrosine Signaling Networks in Epidermal Growth Factor Receptor Overexpressing Squamous Carcinoma Cells Mol. Cell. Proteomics, April 1, 2005; 4(4): 356 - 376. [Abstract] [Full Text] [PDF]

				D. McKillop, E. A. Partridge, J. V. Kemp, M. P. Spence, J. Kendrew, S. Barnett, P. G. Wood, P. B. Giles, A. B. Patterson, F. Bichat, et al. Tumor penetration of gefitinib (Iressa), an epidermal growth factor receptor tyrosine kinase inhibitor Mol. Cancer Ther., April 1, 2005; 4(4): 641 - 649. [Abstract] [Full Text] [PDF]

				C. Zanchi, V. Zuco, C. Lanzi, R. Supino, and F. Zunino Modulation of Survival Signaling Pathways and Persistence of the Genotoxic Stress as a Basis for the Synergistic Interaction between the Atypical Retinoid ST1926 and the Epidermal Growth Factor Receptor Inhibitor ZD1839 Cancer Res., March 15, 2005; 65(6): 2364 - 2372. [Abstract] [Full Text] [PDF]

				S. Kobayashi, T. J. Boggon, T. Dayaram, P. A. Janne, O. Kocher, M. Meyerson, B. E. Johnson, M. J. Eck, D. G. Tenen, and B. Halmos EGFR Mutation and Resistance of Non-Small-Cell Lung Cancer to Gefitinib N. Engl. J. Med., February 24, 2005; 352(8): 786 - 792. [Abstract] [Full Text] [PDF]

				J. P. Spano, R. Fagard, J.-C. Soria, O. Rixe, D. Khayat, and G. Milano Epidermal growth factor receptor signaling in colorectal cancer: preclinical data and therapeutic perspectives Ann. Onc., February 1, 2005; 16(2): 189 - 194. [Abstract] [Full Text] [PDF]