Epidermal growth factor receptor (HER1) tyrosine kinase inhibitor ZD1839 (Iressa) inhibits HER2/neu (erbB2)-overexpressing breast cancer cells in vitro and in vivo

Stacy L. Moulder, F. Michael Yakes, Roberto Bianco, Carlos L. Arteaga, Carlos L. Arteaga, Jean F. Simpson, Carlos L. Arteaga, Senthil K. Muthuswamy

Research output: Contribution to journalArticle

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Abstract

Aberrrant signaling by the epidermal growth factor receptor [EGFR (HER1, erbB1)] and/or HER2/neu tyrosine kinases is present in a cohort of breast carcinomas. Because HER2 is constitutively phosphorylated in some breast tumors, we speculated that, in these cancers, transmodulation of HER2 may occur via EGFR signaling. To test this possibility, we examined the effect of EGFR-specific kinase inhibitors against the HER2-overexpressing human breast tumor lines BT-474, SKBR-3, MDA-361, and MDA-453. ZD1839 (Iressa) is an ATP-mimetic that inhibits the purified EGFR and HER2 kinases in vitro with an IC50 of 0.033 and >3.7 μM, respectively. The specificity of ZD1839 against EGFR was confirmed in Rat1 fibroblasts transfected with EGFR or HER2 chimeric receptors activated by synthetic ligands without the interference of endogenous receptors. Treatment of all breast cancer cell lines (except MDA-453) with 1 μM ZD1839 almost completely eliminated HER2 phosphorylation. In contrast, the incorporation of [γ32P] in vitro onto HER2 receptors isolated from BT-474 cells was unaffected by 1 μM ZD1839. EGFR is expressed by BT-474, SKBR-3, and MDA-361 but not by MDA-453 cells, suggesting that ZD1839-mediated inhibition of the EGFR kinase explained the inhibition 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-3 and BT-474 cells, treatment with ZD1839 plus Herceptin induced a greater apoptotic effect than either inhibitor alone. Finally, ZD1839 completely prevented growth of BT-474 xenografts established in nude mice and enhanced the antitumor effect of Herceptin. These data imply that EGFR tyrosine kinase inhibitors will be effective against HER2-overexpressing breast tumor cells that also express EGFR and support their use in combination with HER2 antibodies, such as Herceptin, against mammary carcinomas with high levels of the HER2 proto-oncogene.

Original languageEnglish (US)
Pages (from-to)8887-8895
Number of pages9
JournalCancer Research
Volume61
Issue number24
StatePublished - Dec 15 2001

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Epidermal Growth Factor Receptor
Protein-Tyrosine Kinases
Breast Neoplasms
Phosphotransferases
Phosphorylation
Artificial Receptors
In Vitro Techniques
gefitinib
Proto-Oncogenes
Growth
Heterografts
Nude Mice
Inhibitory Concentration 50
Fibroblasts
Adenosine Triphosphate
Monoclonal Antibodies
Ligands
Cell Line
Trastuzumab
Antibodies

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Moulder, S. L., Yakes, F. M., Bianco, R., Arteaga, C. L., Arteaga, C. L., Simpson, J. F., ... Muthuswamy, S. K. (2001). Epidermal growth factor receptor (HER1) tyrosine kinase inhibitor ZD1839 (Iressa) inhibits HER2/neu (erbB2)-overexpressing breast cancer cells in vitro and in vivo. Cancer Research, 61(24), 8887-8895.

Epidermal growth factor receptor (HER1) tyrosine kinase inhibitor ZD1839 (Iressa) inhibits HER2/neu (erbB2)-overexpressing breast cancer cells in vitro and in vivo. / Moulder, Stacy L.; Yakes, F. Michael; Bianco, Roberto; Arteaga, Carlos L.; Arteaga, Carlos L.; Simpson, Jean F.; Arteaga, Carlos L.; Muthuswamy, Senthil K.

In: Cancer Research, Vol. 61, No. 24, 15.12.2001, p. 8887-8895.

Research output: Contribution to journalArticle

Moulder, SL, Yakes, FM, Bianco, R, Arteaga, CL, Arteaga, CL, Simpson, JF, Arteaga, CL & Muthuswamy, SK 2001, 'Epidermal growth factor receptor (HER1) tyrosine kinase inhibitor ZD1839 (Iressa) inhibits HER2/neu (erbB2)-overexpressing breast cancer cells in vitro and in vivo', Cancer Research, vol. 61, no. 24, pp. 8887-8895.
Moulder, Stacy L. ; Yakes, F. Michael ; Bianco, Roberto ; Arteaga, Carlos L. ; Arteaga, Carlos L. ; Simpson, Jean F. ; Arteaga, Carlos L. ; Muthuswamy, Senthil K. / Epidermal growth factor receptor (HER1) tyrosine kinase inhibitor ZD1839 (Iressa) inhibits HER2/neu (erbB2)-overexpressing breast cancer cells in vitro and in vivo. In: Cancer Research. 2001 ; Vol. 61, No. 24. pp. 8887-8895.
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abstract = "Aberrrant signaling by the epidermal growth factor receptor [EGFR (HER1, erbB1)] and/or HER2/neu tyrosine kinases is present in a cohort of breast carcinomas. Because HER2 is constitutively phosphorylated in some breast tumors, we speculated that, in these cancers, transmodulation of HER2 may occur via EGFR signaling. To test this possibility, we examined the effect of EGFR-specific kinase inhibitors against the HER2-overexpressing human breast tumor lines BT-474, SKBR-3, MDA-361, and MDA-453. ZD1839 (Iressa) is an ATP-mimetic that inhibits the purified EGFR and HER2 kinases in vitro with an IC50 of 0.033 and >3.7 μM, respectively. The specificity of ZD1839 against EGFR was confirmed in Rat1 fibroblasts transfected with EGFR or HER2 chimeric receptors activated by synthetic ligands without the interference of endogenous receptors. Treatment of all breast cancer cell lines (except MDA-453) with 1 μM ZD1839 almost completely eliminated HER2 phosphorylation. In contrast, the incorporation of [γ32P] in vitro onto HER2 receptors isolated from BT-474 cells was unaffected by 1 μM ZD1839. EGFR is expressed by BT-474, SKBR-3, and MDA-361 but not by MDA-453 cells, suggesting that ZD1839-mediated inhibition of the EGFR kinase explained the inhibition 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-3 and BT-474 cells, treatment with ZD1839 plus Herceptin induced a greater apoptotic effect than either inhibitor alone. Finally, ZD1839 completely prevented growth of BT-474 xenografts established in nude mice and enhanced the antitumor effect of Herceptin. These data imply that EGFR tyrosine kinase inhibitors will be effective against HER2-overexpressing breast tumor cells that also express EGFR and support their use in combination with HER2 antibodies, such as Herceptin, against mammary carcinomas with high levels of the HER2 proto-oncogene.",
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AU - Bianco, Roberto

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AU - Simpson, Jean F.

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