SAN FRANCISCOEarly research suggests that the epidermal growth factor receptor (EGFR) inhibitor Iressa (ZD1839, investigational) may have therapeutic potential in tamoxifen(Drug information on tamoxifen) (Nolvadex)-resistant breast cancer, according to a presentation at the 37th Annual Meeting of the American Society of Clinical Oncology (ASCO abstract 282).
Although many estrogen-receptor-positive breast cancers respond initially to tamoxifen, responses are frequently followed by tumor regrowth attributable to acquired tamoxifen resistance, said J.M. Gee, PhD, Tenovus Centre for Cancer Research, Cardiff, UK. The antiestrogen-resistant phase of the disease, she said, is also associated with over-expression of EGFR and/or EGFR ligands.
Dr. Gee looked at tamoxifen-resistant (R-MCF-7) and wild-type tamoxifen-sensitive (MCF-7) breast cancer cell lines. She found that, like patients with acquired tamoxifen resistance, the R-MCF-7 cells showed markedly elevated mRNA and protein expression of EGFR and HER-2, compared with the wild type cells.
The model was further validated when it was seen that priming with exogenous EGFR ligands increased activation of EGFR signaling elements and induced substantial growth response, Dr. Gee said. Analysis showed that EGFR signaling is critically important to the growth of R-MCF-7 breast cancer cells. Further investigations showed that Iressa efficiently blocked activation of EGFR signaling elements in the R-MCF-7 cells.
After 7 days, concentrations of 1 µM of Iressa in R-MCF-7 cells caused complete inhibition of EGFR and almost total cell growth arrest (90%), reducing cells in S phase and causing accumulation of cells in the G0 and G1 phase of the cell cycle. Growth inhibitory effects in wild type cells were much lower (15%).
Dr. Gee pointed out also that the growth inhibitory effects of Iressa on the R-MCF-7 cells persisted for more than 6 months, indicating that the autocrine EGFR loop is critical to the growth of tamoxifen-resistant cells, and that no other mitogenic network is readily available to them when EGFR signaling is blocked.
Experiments with dual treatment (Iressa plus tamoxifen) suggested further utility. Treating wild type cells with tamoxifen alone caused substantial growth arrest for 1 month followed by regrowth. After dual treatment, however, there was no proliferation at 3 months. "You get superior cell growth arrest and induction of apoptosis," she said.