Abstract
The human EGF (HER) family of receptors has been pursued as therapeutic targets in breast cancer and other malignancies. Trastuzumab and lapatinib are standard treatments for HER2-amplified breast cancer, but a significant number of patients do not respond or develop resistance to these drugs. Here we evaluate the in vitro activity of dacomitinib (PF-00299804), an irreversible small molecule pan-HER inhibitor, in a large panel of human breast cancer cell lines with variable expression of the HER family receptors and ligands, and with variable sensitivity to trastuzumab and lapatinib. Forty-seven human breast cancer and immortalized breast epithelial lines representing the known molecular subgroups of breast cancer were treated with dacomitinib to determine IC(50) values. HER2-amplified lines were far more likely to respond to dacomitinib than nonamplified lines (RR, 3.39; P < 0.0001). Furthermore, HER2 mRNA and protein expression were quantitatively associated with response. Dacomitinib reduced the phosphorylation of HER2, EGFR, HER4, AKT, and ERK in the majority of sensitive lines. Dacomitinib exerted its antiproliferative effect through a combined G(0)-G(1) arrest and an induction of apoptosis. Dacomitinib inhibited growth in several HER2-amplified lines with de novo and acquired resistance to trastuzumab. Dacomitinib maintained a high activity in lines with acquired resistance to lapatinib. This study identifies HER2-amplified breast cancer lines as most sensitive to the antiproliferative effect of dacomitinib and provides a strong rationale for its clinical testing in HER2-amplified breast cancers resistant to trastuzumab and lapatinib.
Highlights
The HER (ErbB) receptor family consists of 4 type I receptor tyrosine kinases, which include the EGF receptor (EGFR, HER1, and ErbB-1), HER2 (HER2/neu, ErbB-2), HER3 (ErbB-3), and HER4 (ErbB-4), and their associated ligands, including EGF, neuregulins (NRG14), TGF-a, amphiregulin, betacellulin, heparin-binding EGF-like growth factor and epiregulin
The HER2-amplified cell lines were most sensitive to growth inhibition by dacomitinib (IC50 < 1 mmol/L in 14 of 16 lines; 87.5%) as compared with 5 of 28 (17.9%) of HER2-nonamplified lines
HER2-amplified lines were far more likely to be classified as responders to dacomitinib [RR, 3.39; 95% confidence interval (CI), 1.82–6.33; P < 0.0001]
Summary
The HER (ErbB) receptor family consists of 4 type I receptor tyrosine kinases, which include the EGF receptor (EGFR, HER1, and ErbB-1), HER2 (HER2/neu, ErbB-2), HER3 (ErbB-3), and HER4 (ErbB-4), and their associated ligands, including EGF, neuregulins (NRG14), TGF-a, amphiregulin, betacellulin, heparin-binding EGF-like growth factor and epiregulin. Ligand binding to the extracellular domain leads to homodimerization or heterodimerization of the receptors and autophosphorylation within the intracellular domain. This results in the activation of signaling cascades involved in mediating cell growth and differentiation. Other family members, HER2 has no known ligand and, under normal conditions, relies on forming heterodimers with other family members that have ligand interactions. In cancer, this tight regulation of HER family signaling is disrupted and contributes to transformation [1]
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