- Paper Report
- Open Access
Iressa inhibits growth of HER-2-overexpressing cells
- Fatima Cardoso1
© Biomed Central Ltd 2001
- Received: 2 November 2001
- Accepted: 8 November 2001
- Published: 1 December 2001
- Breast cancer, HER-2, Iressa
ZD1839 or Iressa is a quinazoline tyrosine kinase inhibitor selective for the epidermal growth factor receptor (EGFR). Due to its oral bioavailability and antitumor activity against a broad range of mouse xenograft models, it was selected for clinical development and has now reached phase II-III clinical trials. Although it selectively inhibits EGFR, the molecular bases for the sensitivity to this compound are not fully understood. EGFR overexpression alone does not seem to be neither sufficient nor indispensable for tumor sensitivity to Iressa.
The authors found that within a panel of human breast cancer and other epithelial tumor cell lines, HER-2-overexpressing tumors were the most sensitive to ZD1839 (even more that EGFR-overexpressing cell lines). The growth inhibition of these tumor cell lines was associated with the dephosphorylation of EGFR, HER-2, and HER-3, the downregulation of Akt activity, and with the loss of association between HER-3 and PI3K (phospohatidylinositol 3-kinase). Furthermore, downregulation of the PI3K/Akt pathway was found to be the best correlate of tumor sensitivity to Iressa, and could be used as a marker of response to this drug. A preliminary in vitro evaluation of the efficacy of the monoclonal antibody anti-HER-2 trastuzumab (HerceptinT) in combination with ZD1839 was performed; the growth inhibitory activities of these two agents were found to be additive.
Tumor cell lines, western blot, immunoblot analysis, autoradiograms, immunoprecipitation