Simiczyjew Aleksandra, Dratkiewicz Ewelina, Van Troys Marleen, Ampe Christophe, Styczeń Ilona, Nowak Dorota
Department of Cell Pathology, Faculty of Biotechnology, University of Wroclaw, Joliot-Curie 14a, 50-383 Wroclaw, Poland.
Department of Biochemistry, Faculty of Medicine and Health Sciences, Ghent University, Albert Baertsoenkaai 3, B-9000 Ghent, Belgium.
Cancers (Basel). 2018 Sep 17;10(9):335. doi: 10.3390/cancers10090335.
Triple-negative breast cancer (TNBC) is the most challenging subtype to treat due to the lack of estrogen receptor, progesterone receptor, and HER2 expression, which excludes the usage of directed targeted therapy against them. Promising therapeutic targets are the hepatocyte growth factor receptor (MET) and epidermal growth factor receptor (EGFR), which expression is frequently elevated in TNBC. Inhibitors of these receptors used as monotherapy are often ineffective. Due to that, we studied the efficacy of combined therapy targeting MET and EGFR simultaneously. Two TNBC cell lines were treated with lapatinib (a dual EGFR and HER2 inhibitor), foretinib (a MET inhibitor), or a combination of the two. After the inhibitors treatment, we verified the cell viability (XTT assay), distribution of the cell cycle phases, the activation of signaling pathways (Western blotting), distribution of invadopodia, fluorescent gelatin digestion (immunofluorescence), and the invasion capacity of cells. A combination of foretinib and lapatinib effectively reduced the viability of examined cells, led to G2/M arrest and reduction of pAKT. There was also a decreasein number of invadopodia formed by cells, their ability to digest gelatin and reduction of cells migration/invasion capacity. Therapy targeting of both EGFR and MET receptors was much more effective against tested cells than monotherapy. We selected a combination of drugs that could be successfully used against this breast cancer subtype.
三阴性乳腺癌（TNBC）是最难治疗的亚型，因为它缺乏雌激素受体、孕激素受体和HER2表达，这排除了针对它们使用定向靶向治疗的可能性。有前景的治疗靶点是肝细胞生长因子受体（MET）和表皮生长因子受体（EGFR），它们在TNBC中的表达经常升高。用作单一疗法的这些受体抑制剂往往无效。因此，我们研究了同时靶向MET和EGFR的联合疗法的疗效。用拉帕替尼（一种双重EGFR和HER2抑制剂）、福瑞替尼（一种MET抑制剂）或两者的组合处理两种TNBC细胞系。在抑制剂处理后，我们验证了细胞活力（XTT测定）、细胞周期阶段分布、信号通路的激活（蛋白质印迹法）、侵袭伪足的分布、荧光明胶消化（免疫荧光）以及细胞的侵袭能力。福瑞替尼和拉帕替尼的组合有效地降低了受试细胞的活力，导致G2/M期阻滞并降低了pAKT水平。细胞形成的侵袭伪足数量也减少了，它们消化明胶的能力以及细胞迁移/侵袭能力也降低了。靶向EGFR和MET受体的联合疗法对受试细胞的效果比单一疗法要好得多。我们选择了一种可以成功用于治疗这种乳腺癌亚型的联合用药方案。
