The Mechanism Of FW-04-806Against HER2-overexpressing Breast Cancer Cells And Its Synergistic Effect With Lapatinib

Objective: To study the mechanism of FW-04-806or the combination Lapatinib with FW-04-806had synergistic in HER2-overexpression breast cancer cells. Methods:(1) MTT assay was used for cell proliferation determination in vitro by FW-04-806in HER2-overexpressing cells SKBR3、BT-474、MDA-MB-453.(2) Through FITC/PI double staining detected the apoptotic effect of the FW-04-806on HER2-overexpressing cells.(3) Possible synergism between Lapatinib and FW-04-806in HER2-overexpressing cell lines was evaluated using the CompuSyn Software.(4) Through FITC/PI double staining detected the apoptotic effect of the combination FW-04-806with Lapatinib on HER2-overexpressing cells.(5) Western blot was used to detect apoptosis, PI3K/AKT and Raf/Mek/ERK1/2pathway related protein level.(6) By xenograft models detected antitumor activity of FW-04-806and Lapatinib in SKBR3tumor.(7) Tumors were used for immunohistochemical evaluation of HER2level.Results:(1) FW-04-806showed inhibition of HER2-overexpressing breast cancer cells in dose-dependent proliferation.(2) FW-04-806induced apoptosis in HER2-overexpressing breast cancer.(3) Synergistic inhibited HER2-overexpressing breast cancer cell lines growth when treated with FW-04-806and Lapatinib.(4) Dramatically induced apoptosis in HER2-overexpressing breast cancer when treated with Lapatinib and FW-04-806.(5) Combining FW-04-806with Lapatinib enhanced inhibition the PI3K/AKT survival pathway and Ras/MEK/ERK growth and proliferation pathway.(6) In vivo, FW-04-806in combination with Lapatinib also had greater antitumor efficacy on tumor xenografts than single-agent.(7) In vivo, FW-04-806in combination with Lapatinib also had greater blocked PI3K/AKT survival pathway and Ras-Raf-MAPK growth and proliferation pathway.(8) By immunohistochemistry show the FW-04-806combination with Lapatinib obviously reducing HER2expression in SKBR3tumors. Conclusion: The current data indicate a synergistic interaction between Lapatinib and FW-04-806in vitro and in vivo. In addition, it can block PI3K/AKT and Ras-Raf-MAPK pathway. So, we suggest that FW-04-806either as a single agent or in combination with Lapatinib support the ongoing clinical investigation in patients with HER2-overexpressing diseases.