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[Cancer Research 61, 7184-7188, October 1, 2001]
© 2001 American Association for Cancer Research

Experimental Therapeutics

The Tyrosine Kinase Inhibitor ZD1839 ("Iressa") Inhibits HER2-driven Signaling and Suppresses the Growth of HER2-overexpressing Tumor Cells1

Mark M. Moasser2, Andrea Basso, Steven D. Averbuch and Neal Rosen

Department of Medicine [M. M. M., N. R.] and Program in Cell Biology [N. R.], Memorial Sloan-Kettering Cancer Center, New York, New York 10021; Program in Pharmacology, Weill Graduate School of Medical Sciences of Cornell University, New York, New York 10021 [A. B.]; and AstraZeneca Pharmaceuticals, Wilmington, Delaware 19850 and Macclesfield, Cheshire, United Kingdom SK10 4TG [S. D. A.]

The epidermal growth factor receptor (EGFR) is commonly overexpressed in many human tumors and provides a new target for anticancer drug development. ZD1839 ("Iressa"), a quinazoline tyrosine kinase inhibitor selective for the EGFR, has shown good activity in preclinical studies and in the early phase of clinical trials. However, because it remains unclear which tumor types are the best targets for treatment with this agent, the molecular characteristics that correlate with tumor sensitivity to ZD1839 have been studied. In a panel of human breast cancer and other epithelial tumor cell lines, HER2-overexpressing tumors were particularly sensitive to ZD1839. Growth inhibition of these tumor cell lines was associated with the dephosphorylation of EGFR, HER2, and HER3, accompanied by the loss of association of HER3 with phosphatidylinositol 3-kinase, and down-regulation of Akt activity. These studies suggest that HER2-overexpressing tumors are particularly susceptible to the inhibition of HER family tyrosine kinase signaling and suggest novel strategies to treat these particularly aggressive tumors.




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Y. H. Kim, G. Ishii, K. Goto, K. Nagai, K. Tsuta, S. Shiono, J. Nitadori, T. Kodama, Y. Nishiwaki, and A. Ochiai
Dominant Papillary Subtype Is a Significant Predictor of the Response to Gefitinib in Adenocarcinoma of the Lung
Clin. Cancer Res., November 1, 2004; 10(21): 7311 - 7317.
[Abstract] [Full Text] [PDF]

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 JCOHome page
J. E. Thompson and C. B. Thompson
Putting the Rap on Akt
J. Clin. Oncol., October 15, 2004; 22(20): 4217 - 4226.
[Abstract] [Full Text] [PDF]

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 Molecular Cancer TherapeuticsHome page
C. D. Britten
Targeting ErbB receptor signaling: A pan-ErbB approach to cancer
Mol. Cancer Ther., October 1, 2004; 3(10): 1335 - 1342.
[Abstract] [Full Text] [PDF]

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 Clin. Cancer Res.Home page
B. Friedmann, M. Caplin, J. A. Hartley, and D. Hochhauser
Modulation of DNA Repair In vitro after Treatment with Chemotherapeutic Agents by the Epidermal Growth Factor Receptor Inhibitor Gefitinib (ZD1839)
Clin. Cancer Res., October 1, 2004; 10(19): 6476 - 6486.
[Abstract] [Full Text] [PDF]

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 Clin. Cancer Res.Home page
P. Matar, F. Rojo, R. Cassia, G. Moreno-Bueno, S. Di Cosimo, J. Tabernero, M. Guzman, S. Rodriguez, J. Arribas, J. Palacios, et al.
Combined Epidermal Growth Factor Receptor Targeting with the Tyrosine Kinase Inhibitor Gefitinib (ZD1839) and the Monoclonal Antibody Cetuximab (IMC-C225): Superiority Over Single-Agent Receptor Targeting
Clin. Cancer Res., October 1, 2004; 10(19): 6487 - 6501.
[Abstract] [Full Text] [PDF]

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V. Gregorc, G. L. Ceresoli, I. Floriani, A. Spreafico, K. B. Bencardino, V. Ludovini, L. Pistola, Z. Mihaylova, F. R. Tofanetti, M. Ferraldeschi, et al.
Effects of Gefitinib on Serum Epidermal Growth Factor Receptor and HER2 in Patients with Advanced Non-Small Cell Lung Cancer
Clin. Cancer Res., September 15, 2004; 10(18): 6006 - 6012.
[Abstract] [Full Text] [PDF]

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 Clin. Cancer Res.Home page
Y. Kuwahara, H. Hosoi, S. Osone, M. Kita, T. Iehara, H. Kuroda, and T. Sugimoto
Antitumor Activity of Gefitinib in Malignant Rhabdoid Tumor Cells In vitro and In vivo
Clin. Cancer Res., September 1, 2004; 10(17): 5940 - 5948.
[Abstract] [Full Text] [PDF]

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 JNCI J Natl Cancer InstHome page
F. Cappuzzo, E. Magrini, G. L. Ceresoli, S. Bartolini, E. Rossi, V. Ludovini, V. Gregorc, C. Ligorio, A. Cancellieri, S. Damiani, et al.
Akt Phosphorylation and Gefitinib Efficacy in Patients With Advanced Non-Small-Cell Lung Cancer
J Natl Cancer Inst, August 4, 2004; 96(15): 1133 - 1141.
[Abstract] [Full Text] [PDF]

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A. R. Tan, X. Yang, S. M. Hewitt, A. Berman, E. R. Lepper, A. Sparreboom, A. L. Parr, W. D. Figg, C. Chow, S. M. Steinberg, 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., August 1, 2004; 22(15): 3080 - 3090.
[Abstract] [Full Text] [PDF]

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 Cancer Res.Home page
S. Huang, E. A. Armstrong, S. Benavente, P. Chinnaiyan, and P. M. Harari
Dual-Agent Molecular Targeting of the Epidermal Growth Factor Receptor (EGFR): Combining Anti-EGFR Antibody with Tyrosine Kinase Inhibitor
Cancer Res., August 1, 2004; 64(15): 5355 - 5362.
[Abstract] [Full Text] [PDF]

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 JNCI J Natl Cancer InstHome page
J. Shou, S. Massarweh, C. K. Osborne, A. E. Wakeling, S. Ali, H. Weiss, and R. Schiff
Mechanisms of Tamoxifen Resistance: Increased Estrogen Receptor-HER2/neu Cross-Talk in ER/HER2-Positive Breast Cancer
J Natl Cancer Inst, June 16, 2004; 96(12): 926 - 935.
[Abstract] [Full Text] [PDF]

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F. Cappuzzo
In Reply:
J. Clin. Oncol., May 15, 2004; 22(10): 2036 - 2037.
[Full Text] [PDF]

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N. Normanno, M. Di Maio, F. Perrone, and M. Campiglio
Molecular Markers to Predict Response to Gefitinib: EGFR, ErbB-2, or More?
J. Clin. Oncol., May 15, 2004; 22(10): 2035 - 2036.
[Full Text] [PDF]

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 Clin. Cancer Res.Home page
C. A. Learn, T. L. Hartzell, C. J. Wikstrand, G. E. Archer, J. N. Rich, A. H. Friedman, H. S. Friedman, D. D. Bigner, and J. H. Sampson
Resistance to Tyrosine Kinase Inhibition by Mutant Epidermal Growth Factor Receptor Variant III Contributes to the Neoplastic Phenotype of Glioblastoma Multiforme
Clin. Cancer Res., May 1, 2004; 10(9): 3216 - 3224.
[Abstract] [Full Text] [PDF]

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 Molecular Cancer TherapeuticsHome page
M. Ono, A. Hirata, T. Kometani, M. Miyagawa, S.-i. Ueda, H. Kinoshita, T. Fujii, and M. Kuwano
Sensitivity to gefitinib (Iressa, ZD1839) in non-small cell lung cancer cell lines correlates with dependence on the epidermal growth factor (EGF) receptor/extracellular signal-regulated kinase 1/2 and EGF receptor/Akt pathway for proliferation
Mol. Cancer Ther., April 1, 2004; 3(4): 465 - 472.
[Abstract] [Full Text] [PDF]

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C. Warburton, W. H. Dragowska, K. Gelmon, S. Chia, H. Yan, D. Masin, T. Denyssevych, A. E. Wallis, and M. B. Bally
Treatment of HER-2/neu Overexpressing Breast Cancer Xenograft Models with Trastuzumab (Herceptin) and Gefitinib (ZD1839): Drug Combination Effects on Tumor Growth, HER-2/neu and Epidermal Growth Factor Receptor Expression, and Viable Hypoxic Cell Fraction
Clin. Cancer Res., April 1, 2004; 10(7): 2512 - 2524.
[Abstract] [Full Text] [PDF]

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V. A. Miller, M. G. Kris, N. Shah, J. Patel, C. Azzoli, J. Gomez, L. M. Krug, W. Pao, N. Rizvi, B. Pizzo, et al.
Bronchioloalveolar Pathologic Subtype and Smoking History Predict Sensitivity to Gefitinib in Advanced Non-Small-Cell Lung Cancer
J. Clin. Oncol., March 15, 2004; 22(6): 1103 - 1109.
[Abstract] [Full Text] [PDF]

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R. S. Herbst, G. Giaccone, J. H. Schiller, R. B. Natale, V. Miller, C. Manegold, G. Scagliotti, R. Rosell, I. Oliff, J. A. Reeves, et al.
Gefitinib in Combination With Paclitaxel and Carboplatin in Advanced Non-Small-Cell Lung Cancer: A Phase III Trial--INTACT 2
J. Clin. Oncol., March 1, 2004; 22(5): 785 - 794.
[Abstract] [Full Text] [PDF]

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 The OncologistHome page
R. Perez-Soler
HER1/EGFR Targeting: Refining the Strategy
Oncologist, February 1, 2004; 9(1): 58 - 67.
[Abstract] [Full Text] [PDF]

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Z. Yang, R. Bagheri-Yarmand, R.-A. Wang, L. Adam, V. V. Papadimitrakopoulou, G. L. Clayman, A. El-Naggar, R. Lotan, C. J. Barnes, W. K. Hong, et al.
The Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor ZD1839 (Iressa) Suppresses c-Src and Pak1 Pathways and Invasiveness of Human Cancer Cells
Clin. Cancer Res., January 15, 2004; 10(2): 658 - 667.
[Abstract] [Full Text] [PDF]

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F. Ciardiello, R. Bianco, R. Caputo, R. Caputo, V. Damiano, T. Troiani, D. Melisi, F. De Vita, S. De Placido, A. R. Bianco, et al.
Antitumor Activity of ZD6474, a Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibitor, in Human Cancer Cells with Acquired Resistance to Antiepidermal Growth Factor Receptor Therapy
Clin. Cancer Res., January 15, 2004; 10(2): 784 - 793.
[Abstract] [Full Text] [PDF]

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M. Sumitomo, T. Asano, J. Asakuma, T. Asano, A. Horiguchi, and M. Hayakawa
ZD1839 Modulates Paclitaxel Response in Renal Cancer by Blocking Paclitaxel-Induced Activation of the Epidermal Growth Factor Receptor-Extracellular Signal-Regulated Kinase Pathway
Clin. Cancer Res., January 15, 2004; 10(2): 794 - 801.
[Abstract] [Full Text] [PDF]

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C. Lu, C. Speers, Y. Zhang, X. Xu, J. Hill, E. Steinbis, J. Celestino, Q. Shen, H. Kim, S. Hilsenbeck, et al.
Effect of Epidermal Growth Factor Receptor Inhibitor on Development of Estrogen Receptor-Negative Mammary Tumors
J Natl Cancer Inst, December 17, 2003; 95(24): 1825 - 1833.
[Abstract] [Full Text] [PDF]

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M. L. Janmaat and G. Giaccone
Small-Molecule Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors
Oncologist, December 1, 2003; 8(6): 576 - 586.
[Abstract] [Full Text] [PDF]

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 Cancer Res.Home page
W. Xu, X. Yuan, Y. J. Jung, Y. Yang, A. Basso, N. Rosen, E. J. Chung, J. Trepel, and L. Neckers
The Heat Shock Protein 90 Inhibitor Geldanamycin and the ErbB Inhibitor ZD1839 Promote Rapid PP1 Phosphatase-Dependent Inactivation of AKT in ErbB2 Overexpressing Breast Cancer Cells
Cancer Res., November 15, 2003; 63(22): 7777 - 7784.
[Abstract] [Full Text] [PDF]

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Q.-B. She, D. Solit, A. Basso, and M. M. Moasser
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., October 1, 2003; 9(12): 4340 - 4346.
[Abstract] [Full Text] [PDF]

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 Mol. Cell. Biol.Home page
G. Zhang, B. He, and G. F. Weber
Growth Factor Signaling Induces Metastasis Genes in Transformed Cells: Molecular Connection between Akt Kinase and Osteopontin in Breast Cancer
Mol. Cell. Biol., September 15, 2003; 23(18): 6507 - 6519.
[Abstract] [Full Text] [PDF]

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 Ann OncolHome page
G. Atalay, F. Cardoso, A. Awada, and M. J. Piccart
Novel therapeutic strategies targeting the epidermal growth factor receptor (EGFR) family and its downstream effectors in breast cancer
Ann. Onc., September 1, 2003; 14(9): 1346 - 1363.
[Abstract] [Full Text] [PDF]

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Y. She, F. Lee, J. Chen, A. Haimovitz-Friedman, V. A. Miller, V. R. Rusch, M. G. Kris, and F. M. Sirotnak
The Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor ZD1839 Selectively Potentiates Radiation Response of Human Tumors in Nude Mice, with a Marked Improvement in Therapeutic Index
Clin. Cancer Res., September 1, 2003; 9(10): 3773 - 3778.
[Abstract] [Full Text] [PDF]

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L.-A. Martin, I. Farmer, S. R. D. Johnston, S. Ali, C. Marshall, and M. Dowsett
Enhanced Estrogen Receptor (ER) {alpha}, ERBB2, and MAPK Signal Transduction Pathways Operate during the Adaptation of MCF-7 Cells to Long Term Estrogen Deprivation
J. Biol. Chem., August 15, 2003; 278(33): 30458 - 30468.
[Abstract] [Full Text] [PDF]

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M. R. Muller, F. Grunebach, K. Kayser, W. Vogel, A. Nencioni, W. Brugger, L. Kanz, and P. Brossart
Expression of Her-2/neu on Acute Lymphoblastic Leukemias: Implications for the Development of Immunotherapeutic Approaches
Clin. Cancer Res., August 1, 2003; 9(9): 3448 - 3453.
[Abstract] [Full Text] [PDF]

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F. Cappuzzo, V. Gregorc, E. Rossi, A. Cancellieri, E. Magrini, C. T. Paties, G. Ceresoli, L. Lombardo, S. Bartolini, C. Calandri, et al.
Gefitinib in Pretreated Non-Small-Cell Lung Cancer (NSCLC): Analysis of Efficacy and Correlation With HER2 and Epidermal Growth Factor Receptor Expression in Locally Advanced or Metastatic NSCLC
J. Clin. Oncol., July 15, 2003; 21(14): 2658 - 2663.
[Abstract] [Full Text] [PDF]

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B. B.Y. Ma, R. G. Bristow, J. Kim, and L. L. Siu
Combined-Modality Treatment of Solid Tumors Using Radiotherapy and Molecular Targeted Agents
J. Clin. Oncol., July 15, 2003; 21(14): 2760 - 2776.
[Abstract] [Full Text] [PDF]

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J. Mendelsohn and J. Baselga
Status of Epidermal Growth Factor Receptor Antagonists in the Biology and Treatment of Cancer
J. Clin. Oncol., July 15, 2003; 21(14): 2787 - 2799.
[Abstract] [Full Text] [PDF]

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 Clin. Cancer Res.Home page
M. Daneshmand, D. A. E. Parolin, H. W. Hirte, P. Major, G. Goss, D. Stewart, G. Batist, W. H. Miller Jr., S. Matthews, L. Seymour, et al.
A Pharmacodynamic Study of the Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor ZD1839 in Metastatic Colorectal Cancer Patients
Clin. Cancer Res., July 1, 2003; 9(7): 2457 - 2464.
[Abstract] [Full Text] [PDF]

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E. F. Petricoin and L. A. Liotta
Clinical Applications of Proteomics
J. Nutr., July 1, 2003; 133(7): 2476S - 2484.
[Abstract] [Full Text] [PDF]

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 JNCI J Natl Cancer InstHome page
V. Grunwald and M. Hidalgo
Developing Inhibitors of the Epidermal Growth Factor Receptor for Cancer Treatment
J Natl Cancer Inst, June 18, 2003; 95(12): 851 - 867.
[Abstract] [Full Text] [PDF]

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D. H. Johnson and C. L. Arteaga
Gefitinib in Recurrent Non-Small-Cell Lung Cancer: An IDEAL Trial?
J. Clin. Oncol., June 15, 2003; 21(12): 2227 - 2229.
[Full Text] [PDF]

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 Clin. Cancer Res.Home page
M. L. Janmaat, F. A. E. Kruyt, J. A. Rodriguez, and G. Giaccone
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., June 1, 2003; 9(6): 2316 - 2326.
[Abstract] [Full Text] [PDF]

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 Clin. Cancer Res.Home page
C. L. Arteaga and J. Baselga
Clinical Trial Design and End Points for Epidermal Growth Factor Receptor-targeted Therapies: Implications for Drug Development and Practice
Clin. Cancer Res., May 1, 2003; 9(5): 1579 - 1589.
[Full Text] [PDF]

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 J. Clin. Pathol.Home page
A J Lodge, J J Anderson, W J Gullick, B Haugk, R C F Leonard, and B Angus
Type 1 growth factor receptor expression in node positive breast cancer: adverse prognostic significance of c-erbB-4
J. Clin. Pathol., April 1, 2003; 56(4): 300 - 304.
[Abstract] [Full Text] [PDF]

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 Molecular Cancer TherapeuticsHome page
C. J. Barnes, R. Bagheri-Yarmand, M. Mandal, Z. Yang, G. L. Clayman, W. K. Hong, and R. Kumar
Suppression of Epidermal Growth Factor Receptor, Mitogen-activated Protein Kinase, and Pak1 Pathways and Invasiveness of Human Cutaneous Squamous Cancer Cells by the Tyrosine Kinase Inhibitor ZD1839 (Iressa)
Mol. Cancer Ther., April 1, 2003; 2(4): 345 - 351.
[Abstract] [Full Text] [PDF]


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