Abstract
Preclinical studies have shown the potential antitumour efficacy of monoclonal antibodies
(MAbs) directed to the epidermal growth factor receptor (EGFR). In this report, we
investigated the cytotoxic effects of the MAb matuzumab (EMD 72000) towards A431 cells
and compared it to cetuximab. While cetuximab induced cell cycle arrest and inhibited
A431 cell proliferation, matuzumab did not. Both MAbs inhibited growth factor induced
EGFR, HER2 and AKT phosphorylation; however, only cetuximab inhibited ERK 1/2 phosphorylation.
Taken together, the data indicate that each antibody may elicit different responses
on EGFR downstream signalling pathways with a distinct impact on A431 cell line survival.
When combined, MAbs synergistically inhibited cell proliferation and induced EGFR
down-regulation with a strong inhibition of ERK1/2 and AKT phosphorylation. In addition,
both MAbs efficiently inhibited VEGF expression and induced ADCC, highlighting their
therapeutic potential in vivo when used either as a single agent or in combination.
Keywords
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to European Journal of CancerAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Expression of epidermal growth factor receptor and c-erbB2 during the development of tamoxifen resistance in human breast cancer.Clin Cancer Res. 1997; 3: 1643-1651
- Epidermal growth factor receptor dependence in human tumors: more than just expression?.Oncologist. 2002; 7: 31-39
- Untangling the ErbB signalling network.Nat Rev Mol Cell Biol. 2001; 2: 127-137
- Structural basis for inhibition of the epidermal growth factor receptor by cetuximab.Cancer Cell. 2005; 7: 301-311
- Mechanisms of resistance to erbitux (anti-epidermal growth factor receptor) combination therapy in pancreatic adenocarcinoma cells.J Gastrointest Surg. 2004; 8: 960-969
- Combining EGFR inhibitors with radiation or chemotherapy: will preclinical studies predict clinical results?.Int J Radiat Oncol Biol Phys. 2004; 58: 976-983
- 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. 2003; 9: 2316-2326
- The antiepidermal growth factor receptor monoclonal antibody cetuximab/C225 reduces hypoxia-inducible factor-1 alpha, leading to transcriptional inhibition of vascular endothelial growth factor expression.Oncogene. 2005; 24: 4433-4441
- Neutralizing antibodies against epidermal growth factor and ErbB-2/neu receptor tyrosine kinases down-regulate vascular endothelial growth factor production by tumor cells in vitro and in vivo: angiogenic implications for signal transduction therapy of solid tumors.Am J Pathol. 1997; 151: 1523-1530
- Antibody-dependent cellular cytotoxicity of cetuximab against tumor cells with wild-type or mutant epidermal growth factor receptor.Cancer Sci. 2007; 98: 1275-1280
- Cetuximab induce antibody-dependent cellular cytotoxicity against EGFR-expressing esophageal squamous cell carcinoma.Int J Cancer. 2007; 120: 781-787
- Biological impediments to monoclonal antibody-based cancer immunotherapy.Mol Cancer Ther. 2004; 3: 1493-1501
- Technology evaluation: matuzumab, Merck KGaA.Curr Opin Mol Ther. 2004; 6: 96-103
- Clotrimazole decreases human breast cancer cells viability through alterations in cytoskeleton-associated glycolytic enzymes.Mol Genet Metab. 2005; 84: 354-362
- Chemotherapy triggers apoptosis in a caspase-8-dependent and mitochondria-controlled manner in the non-small cell lung cancer cell line NCI-H460.Cancer Res. 2000; 60: 7133-7141
- Epidermal growth factor receptor double targeting by a tyrosine kinase inhibitor (Iressa) and a monoclonal antibody (Cetuximab). Impact on cell growth and molecular factors 2.Brit J Cancer. 2005; 92: 1063-1068
- Modulation of radiation response after epidermal growth factor receptor blockade in squamous cell carcinomas: inhibition of damage repair, cell cycle kinetics, and tumor angiogenesis.Clin Cancer Res. 2000; 6: 2166-2174
- The effects of cetuximab alone and in combination with radiation and/or chemotherapy in lung cancer.Clin Cancer Res. 2005; 11: 795-805
- Analysis of relative gene expression data using real-time quantitative PCR and the 2(-delta delta C(T)) method.Methods. 2001; 25: 402-408
- EGF-ERBB signalling: towards the systems level.Nat Rev Mol Cell Biol. 2006; 7: 505-516
- Synergistic down-regulation of receptor tyrosine kinases by combinations of mAbs: implications for cancer immunotherapy5.Proc Natl Acad Sci USA. 2005; 102: 1915-1920
- Matuzumab binding to EGFR prevents the conformational rearrangement required for dimerization 1.Cancer Cell. 2008; 13: 365-373
- Anti-(epidermal growth factor) receptor monoclonal antibodies for the induction of antibody-dependent cell-mediated cytotoxicity against squamous cell carcinoma lines of the head and neck.Cancer Immunol Immun. 1998; 46: 167-173
- Tumor growth modulation by a monoclonal antibody to the epidermal growth factor receptor: immunologically mediated and effector cell-independent effects.Cancer Res. 1987; 47: 3692-3696
- Matuzumab and cetuximab activate the epidermal growth factor receptor but fail to trigger downstream signaling by Akt or Erk.Int J Cancer. 2008; 122: 1530-1538
- The MEK/MAPK pathway is involved in the resistance of breast cancer cells to the EGFR tyrosine kinase inhibitor gefitinib.J Cell Physiol. 2006; 207: 420-427
- Combined lapatinib and cetuximab enhance cytotoxicity against gefitinib-resistant lung cancer cells.Mol Cancer Ther. 2008; 7: 607-615
- Activated extracellular signal-regulated kinases association with epidermal growth factor receptor/transforming growth factor alfa expression in head and neck squamous carcinoma and inhibition by anti-epidermal growth factor receptor treatments.Cancer Res. 2001; 61: 6500-6510
- Antibody-dependent cellular cytotoxicity mediated by cetuximab against lung cancer cell lines.Clin Cancer Res. 2007; 13: 1552-1561
Article info
Publication history
Published online: January 23, 2009
Accepted:
December 12,
2008
Received in revised form:
December 9,
2008
Received:
June 30,
2008
Identification
Copyright
© 2008 Elsevier Ltd. Published by Elsevier Inc. All rights reserved.
