YES1amplification confers trastuzumab-emtansine (T-DM1) resistance in HER2-positive cancer
文献类型：期刊论文
| 作者 | Wang, Lei; Wang, Quanren; Xu, Piaopiao; Fu, Li; Li, Yun; Fu, Haoyu; Quan, Haitian ; Lou, Liguang
|
| 刊名 | BRITISH JOURNAL OF CANCER
 |
| 出版日期 | 2020-06-23 |
| 页码 | 12 |
| ISSN号 | 0007-0920 |
| DOI | 10.1038/s41416-020-0952-1 |
| 通讯作者 | Quan, Haitian(haitianquan@simm.ac.cn) ; Lou, Liguang(lglou@mail.shcnc.ac.cn) |
| 英文摘要 | Background Trastuzumab-emtansine (T-DM1), one of the most potent HER2-targeted drugs, shows impressive efficacy in patients with HER2-positive breast cancers. However, resistance inevitably occurs and becomes a critical clinical problem. Methods We modelled the development of acquired resistance by exposing HER2-positive cells to escalating concentrations of T-DM1. Signalling pathways activation was detected by western blotting, gene expression was analysed by qRT-PCR and gene copy numbers were determined by qPCR. The role of Yes on resistance was confirmed by siRNA-mediated knockdown and stable transfection-mediated overexpression. The in vivo effects were tested in xenograft model. Results We found that Yes is overexpressed in T-DM1-resistant cells owing to amplification of chromosome region 18p11.32, where theYES1gene resides. Yes activated multiple proliferation-related signalling pathways, including EGFR, PI3K and MAPK, and led to cross-resistance to all types of HER2-targeted drugs, including antibody-drug conjugate, antibody and small molecule inhibitor. The outcome of this cross-resistance may be a clinically incurable condition. Importantly, we found that inhibiting Yes with dasatinib sensitised resistant cells in vitro and in vivo. Conclusions Our study revealed thatYES1amplification conferred resistance to HER2-targeted drugs and suggested the potential application of the strategy of combining HER2 and Yes inhibition in the clinic. |
| WOS关键词 | GROWTH-FACTOR RECEPTOR ; SRC FAMILY KINASES ; CELL LUNG-CANCER ; BREAST-CANCER ; TYROSINE KINASES ; ACQUIRED-RESISTANCE ; TARGETING SRC ; LAPATINIB ; AMPLIFICATION ; CAPECITABINE |
| 资助项目 | National Natural Science Foundation of China[81502636] ; Shanghai Science and Technology Committee[18DZ2293200] ; Yunnan Provincial Science and Technology Department[2017ZF010] |
| WOS研究方向 | Oncology |
| 语种 | 英语 |
| WOS记录号 | WOS:000542070600001 |
| 出版者 | NATURE PUBLISHING GROUP |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/291793]  |
| 专题 | 中国科学院上海药物研究所 |
| 通讯作者 | Quan, Haitian; Lou, Liguang |
| 作者单位 | Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China |
| 推荐引用方式 GB/T 7714 | Wang, Lei,Wang, Quanren,Xu, Piaopiao,et al. YES1amplification confers trastuzumab-emtansine (T-DM1) resistance in HER2-positive cancer[J]. BRITISH JOURNAL OF CANCER,2020:12. |
| APA | Wang, Lei.,Wang, Quanren.,Xu, Piaopiao.,Fu, Li.,Li, Yun.,...&Lou, Liguang.(2020).YES1amplification confers trastuzumab-emtansine (T-DM1) resistance in HER2-positive cancer.BRITISH JOURNAL OF CANCER,12. |
| MLA | Wang, Lei,et al."YES1amplification confers trastuzumab-emtansine (T-DM1) resistance in HER2-positive cancer".BRITISH JOURNAL OF CANCER (2020):12. |
入库方式： OAI收割
来源：上海药物研究所
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