Activity of panitumumab alone or with chemotherapy in non-small cell lung carcinoma cell lines expressing mutant epidermal growth factor receptor.

Abstract

Epidermal growth factor receptor (EGFR) kinase domain mutations cause hyperresponsiveness to ligand and hypersensitivity to small-molecule tyrosine kinase inhibitors. However, little is known about how these mutations respond to antibodies against EGFR. We investigated the activity of panitumumab, a fully human anti-EGFR monoclonal antibody, in vitro in mutant EGFR-expressing non-small cell lung carcinoma (NSCLC) cells and in vivo with chemotherapy in xenograft models. Mutant EGFR-expressing NSCLC cells (NCI-H1975 [L858R+T790M] and NCI-H1650 [Delta746-750]) and CHO cells were treated with panitumumab before EGF stimulation to assess the inhibition of EGFR autophosphorylation. Established tumors were treated with panitumumab (25, 100, or 500 mug/mouse twice a week) alone or with docetaxel (10 or 20 mg/kg once a week) or cisplatin (7.5 mg/kg once a week). Antitumor activity and levels of proliferation markers were analyzed. Treatment of mutant EGFR-expressing CHO and NSCLC cells with panitumumab inhibited ligand-dependent autophosphorylation. In NCI-H1975 and NCI-H1650 xenografts, treatment with panitumumab alone or with cisplatin inhibited tumor growth compared with control (P < 0.0003). With panitumumab plus docetaxel, enhanced antitumor activity was seen in both xenografts versus panitumumab alone. Panitumumab treatment alone decreased Ki-67 and phospho- mitogen-activated protein kinase (pMAPK) staining in both xenografts compared with control. Docetaxel enhanced panitumumab activity in NCI-H1650 xenografts (decreased Ki-67 and pMAPK staining by >60%) when compared with either agent alone. Panitumumab inhibits ligand-induced EGFR phosphorylation, tumor growth, and markers of proliferation alone or with docetaxel in NSCLC cell lines that express clinically observed EGFR kinase domain mutations, including the small-molecule tyrosine kinase inhibitor-resistant T790M mutation.

• Authors: Daniel J Freeman, Tammy Bush, Selam Ogbagabriel, Brian Belmontes, Todd Juan, Cherylene Plewa, Gwyneth Van, Carol Johnson, Robert Radinsky
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 8 Issue 6 Pg. 1536-46 (Jun 2009) ISSN: 1538-8514 [Electronic] United States
• PMID: 19509246 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal
• Ki-67 Antigen
• Taxoids
• Docetaxel
• Panitumumab
• ErbB Receptors
• Mitogen-Activated Protein Kinases
• Cisplatin

Topics

• Animals
• Antibodies, Monoclonal (administration & dosage, pharmacology)
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Blotting, Western
• CHO Cells
• Carcinoma, Non-Small-Cell Lung (drug therapy, genetics, pathology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cisplatin (administration & dosage)
• Cricetinae
• Cricetulus
• Docetaxel
• ErbB Receptors (genetics, immunology, metabolism)
• Humans
• Immunohistochemistry
• Ki-67 Antigen (metabolism)
• Lung Neoplasms (drug therapy, genetics, pathology)
• Mice
• Mice, Nude
• Mitogen-Activated Protein Kinases (metabolism)
• Mutation
• Panitumumab
• Phosphorylation (drug effects)
• Taxoids (administration & dosage)
• Tumor Burden (drug effects)
• Xenograft Model Antitumor Assays