舒林酸衍生物K-80003与MEK抑制剂考比替尼联合用药对乳腺癌的效果研究

Effect of sulindac derivative K-80003 in combination with MEK inhibitor cobimetinib in breast cancer cells

目的舒林酸衍生物K-80003是全球首个以类维甲酸受体的截断形式(该文简称tRXRα)为靶点的原创候选新药。本课题组前期研究发现,K-80003在抑制乳腺癌的同时,在乳腺癌细胞中可以激活p-ERK,因此该文试图将K-80003与已上市的MEK抑制剂考比替尼(cobimetinib,GDC-0973)联合使用,探究其对乳腺癌的抑制效果是否增强。方法采用Western blot法、MMTV-PyMT乳腺癌转基因小鼠模型、免疫组化染色等方法,检测K-80003与GDC-0973联合用药对乳腺癌细胞内ERK信号通路及肿瘤细胞凋亡水平的影响。结果 K-80003与GDC-0973联合使用可以更好地抑制p-ERK,并促进PARP切割,导致乳腺癌细胞凋亡,K-80003与GDC-0973联合使用相比于K-80003单药使用,对肿瘤细胞增殖的抑制作用有明显统计学意义。结论舒林酸衍生物K-80003与MEK抑制剂GDC-0973联合使用呈现一定的协同促进乳腺癌细胞凋亡作用。

Aim To determine whether the inhibition of K-80003-activated p-ERK could potentiate the anti-cancer effect of K-80003 in vitro and in vivo . Methods The effects of K-80003 in combination with the MEK inhibitor cobimetinib on ERK activation and tumor cell apoptosis in breast cancer cells were detected by Western blot and immunohistochemical staining in MCF-7 breast cancer cells and MMTV-PyMT mammary transgenic mice. Results K-80003 activation of ERK in MCF-7 breast cancer cells and in MMTV-PyMT mammary transgenic mice was strongly inhibited by co-treatment with cobimetinib. The co-treatment also resulted in a strong induction of apoptosis and inhibition of the growth of tumor cells in vitro and in animals, as compared with K-80003 alone. It was detected that K-80003 in combination with cobimetinib synergistically inhibited the growth of MMTV-PyMT tumor strongly, suggesting that K-80003 activation of ERK serves as an escape mechanism by which tumor cells develop resistance to K-80003 treatment. Conclusion An attractive approach is identified to enhance the therapeutic effect of K-80003 and to overcome potential resistance associated with the K-80003 therapy.