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1 Division of Hematology/Oncology and 2 Division of Pulmonary and Critical Care Medicine, Department of Medicine, Case Western Reserve University and University Hospitals of Cleveland, Cleveland, OH
Requests for Reprints: Afshin Dowlati, University Hospitals of Cleveland, 11100 Euclid Avenue, Cleveland, OH 44016. Fax: (216) 844-5234. E-mail: axd44@cwru.edu
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.
Key Words: Epidermal growth factor receptor • STAT proteins • epidermoid tumors • lung cancer • A431 cell line
Grant support: K12 CA76917 and R01 HL-60165 from the NIH.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 9/ 3/03; revised 1/ 8/04; accepted 1/27/04.
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