Aberrant intracellular metabolism of T-DM1 confers T-DM1 resistance in human epidermal growth factor receptor 2-positive gastric cancer cells
文献类型：期刊论文
| 作者 | Wang, Hongbin1,2; Wang, Wenqian1; Xu, Yongping1; Yang, Yong1; Chen, Xiaoyan1 ; Quan, Haitian1; Lou, Liguang1
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| 刊名 | CANCER SCIENCE
 |
| 出版日期 | 2017-07 |
| 卷号 | 108期号:7页码:1458-1468 |
| 关键词 | Antibody-drug conjugate drug resistance HER2 T-DM1 V-ATPase |
| ISSN号 | 1349-7006 |
| DOI | 10.1111/cas.13253 |
| 文献子类 | Article |
| 英文摘要 | 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. |
| WOS关键词 | ANTIBODY-DRUG CONJUGATE ; BREAST-CANCER ; TRASTUZUMAB EMTANSINE ; MONOCLONAL-ANTIBODY ; TUMOR-CELLS ; PTEN LOSS ; IN-VIVO ; KINASE ; THERAPY ; LINKER |
| 资助项目 | National Science & Technology Major Project "Key New Drug Creation and Manufacturing Program", China[2013ZX09102008] ; National Natural Science Foundation of China[30801404] ; National Natural Science Foundation of China[81273546] |
| WOS研究方向 | Oncology |
| 语种 | 英语 |
| WOS记录号 | WOS:000404963700021 |
| 出版者 | WILEY |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/272589]  |
| 专题 | 药理学第一研究室 |
| 通讯作者 | Quan, Haitian; Lou, Liguang |
| 作者单位 | 1.Chinese Acad Sci, Shanghai Inst Mat Med, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China; 2.Univ Chinese Acad Sci, Beijing, Peoples R China |
| 推荐引用方式 GB/T 7714 | Wang, Hongbin,Wang, Wenqian,Xu, Yongping,et al. Aberrant intracellular metabolism of T-DM1 confers T-DM1 resistance in human epidermal growth factor receptor 2-positive gastric cancer cells[J]. CANCER SCIENCE,2017,108(7):1458-1468. |
| APA | Wang, Hongbin.,Wang, Wenqian.,Xu, Yongping.,Yang, Yong.,Chen, Xiaoyan.,...&Lou, Liguang.(2017).Aberrant intracellular metabolism of T-DM1 confers T-DM1 resistance in human epidermal growth factor receptor 2-positive gastric cancer cells.CANCER SCIENCE,108(7),1458-1468. |
| MLA | Wang, Hongbin,et al."Aberrant intracellular metabolism of T-DM1 confers T-DM1 resistance in human epidermal growth factor receptor 2-positive gastric cancer cells".CANCER SCIENCE 108.7(2017):1458-1468. |
入库方式： OAI收割
来源：上海药物研究所
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