期刊
CANCER SCIENCE
卷 108, 期 7, 页码 1458-1468出版社
WILEY
DOI: 10.1111/cas.13253
关键词
Antibody-drug conjugate; drug resistance; HER2; T-DM1; V-ATPase
类别
资金
- National Science & Technology Major Project Key New Drug Creation and Manufacturing Program, China [2013ZX09102008]
- National Natural Science Foundation of China [30801404, 81273546]
Trastuzumab emtansine (T-DM1), an antibody-drug conjugate (ADC) consisting of human epidermal growth factor receptor 2 (HER2)-targeted mAb trastuzumab linked to antimicrotubule agent mertansine (DM1), has been approved for the treatment of HER2-positive metastatic breast cancer. Acquired resistance has been a major obstacle to T-DM1 treatment, and mechanisms remain incompletely understood. In the present study, we established a T-DM1-resistant N87-KR cell line from HER2-positive N87 gastric cancer cells to investigate mechanisms of acquired resistance and develop strategies for overcoming it. Although the kinetics of binding, internalization, and externalization of T-DM1 were the same in N87-KR cells and N87 cells, N87-KR was strongly resistant to T-DM1, but remained sensitive to both trastuzumab and DM1. T-DM1 failed to inhibit microtubule polymerization in N87-KR cells. Consistently, lysine-MCC-DM1, the active T-DM1 metabolite that inhibits microtubule polymerization, accumulated much less in N87-KR cells than in N87 cells. Furthermore, lysosome acidification, achieved by vacuolar H+-ATPase (V-ATPase), was much diminished in N87-KR cells. Notably, treatment of sensitive N87 cells with the V-ATPase selective inhibitor bafilomycin A1 induced T-DM1 resistance, suggesting that aberrant V-ATPase activity decreases T-DM1 metabolism, leading to T-DM1 resistance in N87-KR cells. Interestingly, HER2-targeted ADCs containing a protease-cleavable linker, such as hertuzumab-vc-monomethyl auristatin E, were capable of efficiently overcoming this resistance. Our results show for the first time that a decrease in T-DM1 metabolites induced by aberrant V-ATPase activity contributes to T-DM1 resistance, which could be overcome by HER2-targeted ADCs containing different linkers, including a protease-cleavable linker. Accordingly, we propose that V-ATPase activity in lysosomes is a novel biomarker for predicting T-DM1 resistance.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据