The HER2 tyrosine kinase is a direct target of erlotinib (Tarceva™), a potent inhibitor of EGFR/HER1 kinase.
Authors: Laura P. Stabile, Jennifer S. Lyker, Christopher T. Gubish, Jill M. Siegfried
Journal: Cancer Research (2004)

Proc Amer Assoc Cancer Res, Volume 45, 2004 2423 Lung cancer is currently the leading cause of cancer death in U.S. men and women and surgical resection for cure is often only applicable to early-stage disease. Thus, finding new therapeutic treatments for lung cancer is critical. We are interested in targeting both the estrogen receptor (ER) pathway and the epidermal growth factor receptor (EGRR) pathway using the pure antiestrogen, Faslodex (ICI 182,780 or Fluvestrant), and the selective EGFR tyrosine kinase inhibitor, Iressa (ZD1839 or Gefitinib), in lung cancer cells. We have found that EGFR protein expression is down-regulated in response to estrogen and up-regulated in response to Faslodex in vitro which suggests that the EGFR pathway is activated when estrogen is depleted in lung cancer cells. This reciprocal control mechanism for estrogen/EGFR regulation provides an ideal model for studying the combination of these two drugs. Treatment of lung cancer with antiestrogenic drugs could give rise to a population of cells with increased levels of EGFR. Therefore, targeting EGFR in combination with traditional hormone therapy could potentially be of benefit by increasing lung tumor cell death and preventing signaling through this alternate growth pathway. We examined three non-small cell lung cancer cell lines, A549, 201T, and 273T, each expressing different levels of EGFR protein. We examined cell growth using a standard MTS assay and apoptosis using the Apo-ONE™ Homogeneous Caspase-3/7 Assay. Lung cancer cells were exposed to 10nM estrogen and 1ng/ml EGF and either 1μM Faslodex, 1μM Iressa or a combination of these drugs. In all cell lines examined, up to a 90% decrease in cell proliferation with the combination of Faslodex plus Iressa was observed. This was accompanied by a 2-fold increase in apoptosis. To determine the involvement of bidirectional signaling between these two receptors in the lung, levels of phospho-p44/42 MAPK protein were measured over time in response to estrogen and EGF treatment. Rapid signaling responses were observed within five minutes in the lung cancer cell lines indicating the involvement of a membrane or cytoplasmic ER transactivation of EGFR. Iressa and Faslodex treatment inhibited this response. Other intracellular signaling pathways are also being examined. In an in vivo lung tumor xenograft model, the combination of Iressa and Faslodex therapy decreased tumor growth in scid mice by approximately 70%, a more than additive effect compared to each treatment alone. The cross-signaling between the EGFR/ER pathways in the lung along with the recent evidence of striking efficacy of Iressa in female lung cancer patients and the emerging role of estrogens in lung tumorigenesis provides rationale to combine Iressa with antiestrogen therapy for lung cancer treatment. Potentially, these studies will provide the basis for a new type of therapy in selected lung cancer patients. This work was supported by NIH P50CA9045440 SPORE in Lung Cancer.