Combined inhibition of epidermal growth factor receptor and JAK/STAT pathways results in greater growth inhibition in vitro than single agent therapy.

Abstract

Epidermal growth factor receptor (EGFR) inhibition with small molecule tyrosine kinase inhibitors results in antitumor activity in only a minority of patients whose tumors express EGFR. One hypothesis to explain this suboptimal clinical activity is that multiple growth regulatory pathways are abnormal in most EGFR-expressing cancers. Given the importance of Stat-3 signaling pathway in epidermoid tumors, we hypothesized that blocking complementary pathways in an epidermal growth factor (EGF)-driven model of proliferation in the A431 cell line would demonstrate improved antiproliferative activity. Exposure of A431 cells to the EGF results in a significant increase in EGFR and Stat-3 phosphorylation. However, inhibition of EGFR by AG1478 fails to decrease EGF-induced Stat-3 phosphorylation. This suggests that EGF continues to drive Stat-3 phosphorylation through other receptors. Our study suggests that residual ErbB2 activation by EGF, despite EGFR blockade, is responsible for persistent downstream activation of Stat-3. In this setting, combined exposure to an EGFR blocker and Stat-3 blocker (AG490) results in significantly greater tumor growth inhibition than either agent alone. We conclude that targeting multiple pathways (EGFR and JAK/STAT pathways) in EGF-driven tumors may result in greater antiproliferative activity than blocking EGFR alone.

• Authors: Afshin Dowlati, David Nethery, Jeffrey A Kern
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 3 Issue 4 Pg. 459-63 (Apr 2004) ISSN: 1535-7163 [Print] United States
• PMID: 15078989 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• 2C4 antibody
• Antibodies, Monoclonal
• DNA-Binding Proteins
• Enzyme Inhibitors
• Quinazolines
• STAT3 Transcription Factor
• STAT3 protein, human
• Trans-Activators
• Tyrphostins
• alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide
• RTKI cpd
• Epidermal Growth Factor
• ErbB Receptors
• Receptor, ErbB-2

Topics

• Antibodies, Monoclonal (pharmacology)
• Cell Division (drug effects)
• Cell Line, Tumor
• DNA-Binding Proteins (antagonists & inhibitors, metabolism)
• Drug Synergism
• Enzyme Activation (drug effects)
• Enzyme Inhibitors (pharmacology)
• Epidermal Growth Factor (pharmacology)
• ErbB Receptors (antagonists & inhibitors, metabolism)
• Humans
• Inhibitory Concentration 50
• Phosphorylation (drug effects)
• Quinazolines
• Receptor, ErbB-2 (antagonists & inhibitors, metabolism)
• STAT3 Transcription Factor
• Signal Transduction (drug effects)
• Trans-Activators (antagonists & inhibitors, metabolism)
• Tyrphostins (pharmacology)