Combined inhibition of epidermal growth factor receptor and JAK/STAT pathways results in greater growth inhibition in vitro than single agent therapy
Year: 2004
Type: article
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.
Source: Molecular Cancer Therapeutics
Authors: Afshin Dowlati, David Nethery, Jeffrey A. Kern
Language: English
Topic: HER2/EGFR in Cancer Research
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W2274041246