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

Pablo Matar, Federico Rojo, Raúl Cassia, Gema Moreno-Bueno, Serena Di Cosimo, José Tabernero, Marta Guzmán, Sonia Rodriguez, Joaquín Arribas, José Palacios, José Baselga

Research output: Contribution to journalArticle

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Abstract

Purpose: The epidermal growth factor receptor (EGFR) is abnormally activated in cancer and two classes of anti-EGFR agents, monoclonal antibodies and low-molecular-weight tyrosine kinase inhibitors, have shown antitumor activity in patients. Because these two classes of antireceptor agents target the EGFR at different sites, we decided to explore whether the combined administration of gefitinib, a tyrosine kinase inhibitor, and cetuximab, a monoclonal antibody, had superior antitumor activity than either agent given alone. Experimental Design: We studied the effects of the combination of gefitinib and cetuximab in a panel of human cancer cell lines and in an EGFR-dependent human tumor xenograft model (A431). The effects of these two agents on EGFR signaling, proliferation, apoptosis, and vascularization were evaluated. In addition, we analyzed, with cDNA arrays, changes in gene expression profiles induced by both agents. Results: The combined treatment with gefitinib and cetoximab resulted in a synergistic effect on cell proliferation and in superior inhibition of EGFR-dependent signaling and induction of apoptosis. In a series of in vivo experiments, single-agent gefitinib or cetuximab resulted in transient complete tumor remission only at the highest doses. In contrast, suboptimal doses of gefitinib and cetuximab given together resulted in a complete and permanent regression of large tumors. In the combination-treated tumors, there was a superior inhibition of EGFR, mitogen-activated protein kinase, and Akt phosphorylation, as well as greater inhibition of cell proliferation and vascularization and enhanced apoptosis. Using cDNA arrays, we found 59 genes that were coregulated and 45 genes differentially regulated, including genes related to cell proliferation and differentiation, transcription, DNA synthesis and repair, angiogenesis, signaling molecules, cytoskeleton organization, and tumor invasion and metastasis. Conclusions: Our findings suggest both shared and complementary mechanisms of action with gefitinib and cetuximab and support combined EGFR targeting as a clinically exploitable strategy.

Original languageEnglish
Pages (from-to)6487-6501
Number of pages15
JournalClinical Cancer Research
Volume10
Issue number19
DOIs
Publication statusPublished - Oct 1 2004

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Epidermal Growth Factor Receptor
Protein-Tyrosine Kinases
Monoclonal Antibodies
Neoplasms
Cell Proliferation
Apoptosis
Oligonucleotide Array Sequence Analysis
Genes
gefitinib
Cetuximab
Mitogen-Activated Protein Kinases
Cytoskeleton
Transcriptome
Heterografts
DNA Repair
Cell Differentiation
Research Design
Molecular Weight
Phosphorylation
Neoplasm Metastasis

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

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. / Matar, Pablo; Rojo, Federico; Cassia, Raúl; Moreno-Bueno, Gema; Di Cosimo, Serena; Tabernero, José; Guzmán, Marta; Rodriguez, Sonia; Arribas, Joaquín; Palacios, José; Baselga, José.

In: Clinical Cancer Research, Vol. 10, No. 19, 01.10.2004, p. 6487-6501.

Research output: Contribution to journalArticle

Matar, P, Rojo, F, Cassia, R, Moreno-Bueno, G, Di Cosimo, S, Tabernero, J, Guzmán, M, Rodriguez, S, Arribas, J, Palacios, J & Baselga, J 2004, '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', Clinical Cancer Research, vol. 10, no. 19, pp. 6487-6501. https://doi.org/10.1158/1078-0432.CCR-04-0870
Matar, Pablo ; Rojo, Federico ; Cassia, Raúl ; Moreno-Bueno, Gema ; Di Cosimo, Serena ; Tabernero, José ; Guzmán, Marta ; Rodriguez, Sonia ; Arribas, Joaquín ; Palacios, José ; Baselga, José. / 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. In: Clinical Cancer Research. 2004 ; Vol. 10, No. 19. pp. 6487-6501.
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T1 - Combined epidermal growth factor receptor targeting with the tyrosine kinase inhibitor Gefitinib (ZD1839) and the monoclonal antibody Cetuximab (IMC-C225)

T2 - Superiority over single-agent receptor targeting

AU - Matar, Pablo

AU - Rojo, Federico

AU - Cassia, Raúl

AU - Moreno-Bueno, Gema

AU - Di Cosimo, Serena

AU - Tabernero, José

AU - Guzmán, Marta

AU - Rodriguez, Sonia

AU - Arribas, Joaquín

AU - Palacios, José

AU - Baselga, José

PY - 2004/10/1

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N2 - Purpose: The epidermal growth factor receptor (EGFR) is abnormally activated in cancer and two classes of anti-EGFR agents, monoclonal antibodies and low-molecular-weight tyrosine kinase inhibitors, have shown antitumor activity in patients. Because these two classes of antireceptor agents target the EGFR at different sites, we decided to explore whether the combined administration of gefitinib, a tyrosine kinase inhibitor, and cetuximab, a monoclonal antibody, had superior antitumor activity than either agent given alone. Experimental Design: We studied the effects of the combination of gefitinib and cetuximab in a panel of human cancer cell lines and in an EGFR-dependent human tumor xenograft model (A431). The effects of these two agents on EGFR signaling, proliferation, apoptosis, and vascularization were evaluated. In addition, we analyzed, with cDNA arrays, changes in gene expression profiles induced by both agents. Results: The combined treatment with gefitinib and cetoximab resulted in a synergistic effect on cell proliferation and in superior inhibition of EGFR-dependent signaling and induction of apoptosis. In a series of in vivo experiments, single-agent gefitinib or cetuximab resulted in transient complete tumor remission only at the highest doses. In contrast, suboptimal doses of gefitinib and cetuximab given together resulted in a complete and permanent regression of large tumors. In the combination-treated tumors, there was a superior inhibition of EGFR, mitogen-activated protein kinase, and Akt phosphorylation, as well as greater inhibition of cell proliferation and vascularization and enhanced apoptosis. Using cDNA arrays, we found 59 genes that were coregulated and 45 genes differentially regulated, including genes related to cell proliferation and differentiation, transcription, DNA synthesis and repair, angiogenesis, signaling molecules, cytoskeleton organization, and tumor invasion and metastasis. Conclusions: Our findings suggest both shared and complementary mechanisms of action with gefitinib and cetuximab and support combined EGFR targeting as a clinically exploitable strategy.

AB - Purpose: The epidermal growth factor receptor (EGFR) is abnormally activated in cancer and two classes of anti-EGFR agents, monoclonal antibodies and low-molecular-weight tyrosine kinase inhibitors, have shown antitumor activity in patients. Because these two classes of antireceptor agents target the EGFR at different sites, we decided to explore whether the combined administration of gefitinib, a tyrosine kinase inhibitor, and cetuximab, a monoclonal antibody, had superior antitumor activity than either agent given alone. Experimental Design: We studied the effects of the combination of gefitinib and cetuximab in a panel of human cancer cell lines and in an EGFR-dependent human tumor xenograft model (A431). The effects of these two agents on EGFR signaling, proliferation, apoptosis, and vascularization were evaluated. In addition, we analyzed, with cDNA arrays, changes in gene expression profiles induced by both agents. Results: The combined treatment with gefitinib and cetoximab resulted in a synergistic effect on cell proliferation and in superior inhibition of EGFR-dependent signaling and induction of apoptosis. In a series of in vivo experiments, single-agent gefitinib or cetuximab resulted in transient complete tumor remission only at the highest doses. In contrast, suboptimal doses of gefitinib and cetuximab given together resulted in a complete and permanent regression of large tumors. In the combination-treated tumors, there was a superior inhibition of EGFR, mitogen-activated protein kinase, and Akt phosphorylation, as well as greater inhibition of cell proliferation and vascularization and enhanced apoptosis. Using cDNA arrays, we found 59 genes that were coregulated and 45 genes differentially regulated, including genes related to cell proliferation and differentiation, transcription, DNA synthesis and repair, angiogenesis, signaling molecules, cytoskeleton organization, and tumor invasion and metastasis. Conclusions: Our findings suggest both shared and complementary mechanisms of action with gefitinib and cetuximab and support combined EGFR targeting as a clinically exploitable strategy.

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