Additive antitumour effect of the epidermal growth factor receptor tyrosine kinase inhibitor gefitinib (Iressa, ZD1839) and the antioestrogen fulvestrant (Faslodex, ICI 182,780) in breast cancer cells

Abstract

A high expression level of epidermal growth factor receptor (EGFR)/HER1 has been suggested to lead to a shorter survival time and resistance to endocrine therapy in patients with breast cancer. To test the hypothesis that inhibition of the EGFR signalling pathway affects the antitumour effect of endocrine therapy, an EGFR tyrosine kinase inhibitor (EGFR-TKI), gefitinib, and an oestrogen receptor (ER) antagonist, fulvestrant, were administered to human breast cancer cells. A total of five human breast cancer cell lines were used. The effects of single or combined treatments with gefitinib and/or fulvestrant on cell growth, cell cycle progression and apoptosis were analysed. Changes in the expression levels of cyclin-dependent kinase inhibitors, p21 and p27, an antiapoptotic factor, Bcl-2, and a proapoptotic factor, Bax, were also investigated. All cell lines tested were sensitive to gefitinib (50% growth inhibitory concentration, 10 -28.5 mM). Breast cancer cell lines with a high expression level of HER1 or HER2 were more sensitive to gefitinib than the others. Gefitinib induced a significant G1 -S blockade in ER-positive KPL-3C cells. Gefitinib induced significant apoptosis in HER1-overexpressing MDA-MB-231 cells. Gefitinib additively increased the antitumour effect of fulvestrant in all three ER-positive cell lines in a medium supplemented with 17b-oestradiol. The combined treatment promoted cell cycle retardation in KPL-3C cells, which is associated with an upregulation of p21 by fulvestrant and gefitinib, respectively. Apoptosis was associated with downregulation of Bcl-2 by gefitinib in MDA-MB-231 cells. These results suggest an additive interaction between the EGFR-TKI gefitinib and the antioestrogen fulvestrant in ER-positive breast cancer cells.

Breast cancer cells can switch between estrogen receptor α and ErbB signaling and combined treatment against both signaling pathways postpones development of resistance

“…Thus, the rescuing effect of Hrg was mediated through ErbB activation, likely through ErbB3 and/or ErbB4 dimerization with ErbB2. [14,37,38]. Our findings that Hrg is able to restore growth of fulvestrant-treated MCF-7 cells and that MCF-7 sublines with acquired fulvestrant resistance are more sensitive to pan-ErbB inhibition when maintained on fulvestrant suggest that combined treatment targeting ErbB and ERa signaling could be used to prevent or delay development of treatment resistance.…”

Combined Targeting of the Estrogen Receptor and the Epidermal Growth Factor Receptor in Non–Small Cell Lung Cancer Shows Enhanced Antiproliferative Effects

“…A combination of an anti-estrogen with gefitinib, both of which could suppress the G 1 -S cell cycle transition by different mechanisms, could be beneficial. Recent results using breast cancer cells support the use of this combination (25).…”

Inhibition of Intrahepatic Bile Duct Dilation of the Polycystic Kidney Rat with a Novel Tyrosine Kinase Inhibitor Gefitinib

“…It has been suggested that the cell-cycle retardation is mediated by the up-regulation of cyclin-dependent kinase inhibitors p21 and p27. 34,35 The induction of apoptosis is mediated by a decrease in the expression level of an anti-apoptotic protein Bcl-2 36 or by the activation of a proapoptotic protein BAD. 37 In this study, we confirmed that gefitinib induced apoptosis in cultured nontumorous BECs, which was associated with the inhibition of biliary cyst formation.…”