Epidermal Growth Factor Receptor (HER1) Tyrosine Kinase Inhibitor ZD1839 (Iressa) Inhibits HER2/neu (erbB2)-overexpressing Breast Cancer Cells in Vitro and in Vivo

Tumor Biology

Epidermal Growth Factor Receptor (HER1) Tyrosine Kinase Inhibitor ZD1839 (Iressa) Inhibits HER2/neu (erbB2)-overexpressing Breast Cancer Cells in Vitro and in Vivo¹

Stacy L. Moulder², F. Michael Yakes², Senthil K. Muthuswamy³, Roberto Bianco, Jean F. Simpson and Carlos L. Arteaga⁴

Departments of Medicine [S. L. M., F. M. Y., R. B., C. L. A.], Cancer Biology [C. L. A.], Pathology [J. F. S.], and Vanderbilt-Ingram Cancer Center [C. L. A.], Vanderbilt University School of Medicine, Nashville, Tennessee 37232-6307, and Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115 [S. K. M.]

Aberrrant signaling by the epidermal growth factor receptor[EGFR (HER1, erbB1)] and/or HER2/neu tyrosine kinases is presentin a cohort of breast carcinomas. Because HER2 is constitutivelyphosphorylated in some breast tumors, we speculated that, inthese cancers, transmodulation of HER2 may occur via EGFR signaling.To test this possibility, we examined the effect of EGFR-specifickinase inhibitors against the HER2-overexpressing human breasttumor lines BT-474, SKBR-3, MDA-361, and MDA-453. ZD1839 (Iressa)is an ATP-mimetic that inhibits the purified EGFR and HER2 kinasesin vitro with an IC₅₀ of 0.033 and >3.7 µM, respectively.The specificity of ZD1839 against EGFR was confirmed in Rat1fibroblasts transfected with EGFR or HER2 chimeric receptorsactivated by synthetic ligands without the interference of endogenousreceptors. Treatment of all breast cancer cell lines (exceptMDA-453) with 1 µM ZD1839 almost completely eliminatedHER2 phosphorylation. In contrast, the incorporation of [ ${gamma}$ -³²P]ATPin vitro onto HER2 receptors isolated from BT-474 cells wasunaffected by 1 µM ZD1839. EGFR is expressed by BT-474,SKBR-3, and MDA-361 but not by MDA-453 cells, suggesting thatZD1839-mediated inhibition of the EGFR kinase explained theinhibition of HER2 phosphorylation in vivo. In SKBR-3 cells,ZD1839 exhibited a greater growth-inhibitory effect than Herceptin,a monoclonal antibody against the HER2 ectodomain. In both SKBR-3and BT-474 cells, treatment with ZD1839 plus Herceptin induceda greater apoptotic effect than either inhibitor alone. Finally,ZD1839 completely prevented growth of BT-474 xenografts establishedin nude mice and enhanced the antitumor effect of Herceptin.These data imply that EGFR tyrosine kinase inhibitors will beeffective against HER2-overexpressing breast tumor cells thatalso express EGFR and support their use in combination withHER2 antibodies, such as Herceptin, against mammary carcinomaswith high levels of the HER2 proto-oncogene.

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[Abstract] [Full Text] [PDF]

C. Tuccillo, M. Romano, T. Troiani, E. Martinelli, F. Morgillo, F. De Vita, R. Bianco, G. Fontanini, R. A. Bianco, G. Tortora, et al.
Antitumor Activity of ZD6474, a Vascular Endothelial Growth Factor-2 and Epidermal Growth Factor Receptor Small Molecule Tyrosine Kinase Inhibitor, in Combination with SC-236, a Cyclooxygenase-2 Inhibitor
Clin. Cancer Res., February 1, 2005; 11(3): 1268 - 1276.
[Abstract] [Full Text] [PDF]

S. R. Johnston
Combinations of Endocrine and Biological Agents: Present Status of Therapeutic and Presurgical Investigations
Clin. Cancer Res., January 15, 2005; 11(2): 889s - 899s.
[Abstract] [Full Text] [PDF]

M. L. Reyzer, R. L. Caldwell, T. C. Dugger, J. T. Forbes, C. A. Ritter, M. Guix, C. L. Arteaga, and R. M. Caprioli
Early Changes in Protein Expression Detected by Mass Spectrometry Predict Tumor Response to Molecular Therapeutics
Cancer Res., December 15, 2004; 64(24): 9093 - 9100.
[Abstract] [Full Text] [PDF]

P M Harari
Epidermal growth factor receptor inhibition strategies in oncology
Endocr. Relat. Cancer, December 1, 2004; 11(4): 689 - 708.
[Abstract] [Full Text] [PDF]

M. Milella, D. Trisciuoglio, T. Bruno, L. Ciuffreda, M. Mottolese, A. Cianciulli, F. Cognetti, U. Zangemeister-Wittke, D. Del Bufalo, and G. Zupi
Trastuzumab Down-Regulates Bcl-2 Expression and Potentiates Apoptosis Induction by Bcl-2/Bcl-XL Bispecific Antisense Oligonucleotides in HER-2Gene-Amplified Breast Cancer Cells
Clin. Cancer Res., November 15, 2004; 10(22): 7747 - 7756.
[Abstract] [Full Text] [PDF]

L. H. Kalish, R. A. Kwong, I. E. Cole, R. M. Gallagher, R. L. Sutherland, and E. A. Musgrove
Deregulated Cyclin D1 Expression Is Associated with Decreased Efficacy of the Selective Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Gefitinib in Head and Neck Squamous Cell Carcinoma Cell Lines
Clin. Cancer Res., November 15, 2004; 10(22): 7764 - 7774.
[Abstract] [Full Text] [PDF]

S. Tracy, T. Mukohara, M. Hansen, M. Meyerson, B. E. Johnson, and P. A. Janne
Gefitinib Induces Apoptosis in the EGFRL858R Non-Small-Cell Lung Cancer Cell Line H3255
Cancer Res., October 15, 2004; 64(20): 7241 - 7244.
[Abstract] [Full Text] [PDF]

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]

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]

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]

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]

R. E. Brown, M. Lun, J. W. Prichard, T. M. Blasick, and P. L. Zhang
Morphoproteomic and Pharmacoproteomic Correlates in Hormone-Receptor-Negative Breast Carcinoma Cell Lines
Ann. Clin. Lab. Sci., July 1, 2004; 34(3): 251 - 262.
[Abstract] [Full Text] [PDF]

Y. Ueda, S. Wang, N. Dumont, J. Y. Yi, Y. Koh, and C. L. Arteaga
Overexpression of HER2 (erbB2) in Human Breast Epithelial Cells Unmasks Transforming Growth Factor {beta}-induced Cell Motility
J. Biol. Chem., June 4, 2004; 279(23): 24505 - 24513.
[Abstract] [Full Text] [PDF]

H. A. Burris III
Dual Kinase Inhibition in the Treatment of Breast Cancer: Initial Experience with the EGFR/ErbB-2 Inhibitor Lapatinib
Oncologist, June 3, 2004; 9(suppl_3): 10 - 15.
[Abstract] [Full Text] [PDF]

K. D. Miller
The Role of ErbB Inhibitors in Trastuzumab Resistance
Oncologist, June 3, 2004; 9(suppl_3): 16 - 19.
[Abstract] [Full Text] [PDF]

S. K. Rabindran, C. M. Discafani, E. C. Rosfjord, M. Baxter, M. B. Floyd, J. Golas, W. A. Hallett, B. D. Johnson, R. Nilakantan, E. Overbeek, et al.
Antitumor Activity of HKI-272, an Orally Active, Irreversible Inhibitor of the HER-2 Tyrosine Kinase
Cancer Res., June 1, 2004; 64(11): 3958 - 3965.
[Abstract] [Full Text] [PDF]

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.
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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]

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]

G. Yang, K. Q. Cai, J. A. Thompson-Lanza, R. C. Bast Jr., and J. Liu
Inhibition of Breast and Ovarian Tumor Growth through Multiple Signaling Pathways by Using Retrovirus-mediated Small Interfering RNA against Her-2/neu Gene Expression
J. Biol. Chem., February 6, 2004; 279(6): 4339 - 4345.
[Abstract] [Full Text] [PDF]

S. D. Pack, O. M. Alper, K. Stromberg, M. Augustus, M. Ozdemirli, A. M. Miermont, G. Klus, M. Rusin, R. Slack, N. F. Hacker, et al.
Simultaneous Suppression of Epidermal Growth Factor Receptor and c-erbB-2 Reverses Aneuploidy and Malignant Phenotype of a Human Ovarian Carcinoma Cell Line
Cancer Res., February 1, 2004; 64(3): 789 - 794.
[Abstract] [Full Text] [PDF]

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

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]

M. K. Nyati, D. Maheshwari, S. Hanasoge, A. Sreekumar, S. D. Rynkiewicz, A. M. Chinnaiyan, W. R. Leopold, S. P. Ethier, and T. S. Lawrence
Radiosensitization by Pan ErbB Inhibitor CI-1033 in Vitro and in Vivo
Clin. Cancer Res., January 15, 2004; 10(2): 691 - 700.
[Abstract] [Full Text] [PDF]

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]

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]

G. E. Konecny, C. A. Wilson, and D. J. Slamon
Is There a Role for Epidermal Growth Factor Receptor Inhibitors in Breast Cancer Prevention?
J Natl Cancer Inst, December 17, 2003; 95(24): 1813 - 1815.
[Full Text] [PDF]

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]

S. R Shah, T. L Walsh, C. B Williams, and S. A Soefje
Gefitinib (ZD1839, Iressa(R)): a selective epidermal growth factor receptor-tyrosine kinase inhibitor
Journal of Oncology Pharmacy Practice, December 1, 2003; 9(4): 151 - 160.
[Abstract] [PDF]