中国科学院机构知识库网格
Chinese Academy of Sciences Institutional Repositories Grid
首页 机构 成果 学者
  
  1. CAS IR Grid
  2. 上海药物研究所
  3. 中国科学院上海药物研究所
  4. 新药研究国家重点实验室
Adaptive resistance to PI3K alpha-selective inhibitor CYH33 is mediated by genomic and transcriptomic alterations in ESCC cells

文献类型：期刊论文

作者Wang, Yu-xiang4; Zhang, Xu4,5; Ma, Qing-yang1; Hu, Lan-dian1; Zhang, Xi4; Wang, Yi4; Xu, Lan4; Yang, Chun-hao3; Tan, Cun3; Kong, Xiang-yin1
刊名CELL DEATH & DISEASE
出版日期2021-01-14
卷号12期号:1页码:13
ISSN号2041-4889
DOI10.1038/s41419-020-03370-4
通讯作者Ding, Jian(jding@simm.ac.cn) ; Meng, Ling-hua(lhmeng@simm.ac.cn)
英文摘要Phosphoinositide-3 kinase alpha-specific inhibitors (PI3K alpha i) displayed promising potential for the treatment of esophageal squamous cell carcinoma (ESCC) with frequent activation in PI3K signaling. However, acquired resistance is likely to develop and limit the efficacy of PI3K alpha i like other targeted therapies. To identify genomic adaptation to PI3K alpha i, we applied whole-genome sequencing and detected gene mutation and amplification in four lines of ESCC cells established with adapted resistance to a novel PI3K alpha i CYH33. Particularly, HRAS(G12S) mutation was found in KYSE180C cells. Overexpression of HRAS(G12S) in ESCC parental cells rendered resistance to CYH33. By contrast, down-regulation of HRAS(G12S) restored the sensitivity of KYSE180C1 cells to CYH33, and combination of CYH33 and MEK162 displayed synergistic effect against KYSE180C1 cells and xenografts. Furthermore, elevated mTORC1, mitogen-activated protein kinase (MAPK), and c-Myc signaling pathways were found in resistant cells by RNA sequencing and combination of CYH33 and RAD001, MEK162, or OTX015 overcame the resistance to CYH33, which was accompanied with enhanced inhibition on S6, extracellular signal-regulated kinase 1 (ERK), or c-Myc, respectively. Overall, we characterized the adaptations to PI3K alpha i in ESCC cells and identified combinatorial regimens that may circumvent resistance.
WOS关键词SCREENING REVEALS ; LUNG-CANCER ; CARCINOMA ; MUTATION ; COMBINATION ; ACTIVATION ; LANDSCAPE ; MECHANISM ; KINASE ; POTENT
资助项目Personalized Medicines-Molecular Signature-based Drug Discovery and Development, Strategic Priority Research Program of the Chinese Academy of Sciences[XDA12020111] ; Personalized Medicines-Molecular Signature-based Drug Discovery and Development, Strategic Priority Research Program of the Chinese Academy of Sciences[XDA12010204] ; Personalized Medicines-Molecular Signature-based Drug Discovery and Development, Strategic Priority Research Program of the Chinese Academy of Sciences[XDA12050407] ; National Science and Technology Major Project Key New Drug Creation and Manufacturing Program[2018ZX09711002-011-014] ; National Natural Science Foundation of China[81773760] ; National Natural Science Foundation of China[81973345] ; China Postdoctoral Science Foundation[2019M661668]
WOS研究方向Cell Biology
语种英语
WOS记录号WOS:000609814100003
出版者SPRINGERNATURE
源URL[http://119.78.100.183/handle/2S10ELR8/295954]  
专题新药研究国家重点实验室
通讯作者Ding, Jian; Meng, Ling-hua
作者单位1.Chinese Acad Sci, Shanghai Inst Nutr & Hlth, 320 Yueyang Rd, Shanghai 200031, Peoples R China
2.Chinese Acad Sci, Shanghai Inst Mat Med, Div Antitumor Pharmacol, State Key Lab Drug Res, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China
3.Chinese Acad Sci, Shanghai Inst Mat Med, Dept Med Chem, 555 Zuchongzhi Rd, Shanghai 200120, Peoples R China
4.Chinese Acad Sci, Shanghai Inst Mat Med, Div Antitumor Pharmacol, 501 Haike Rd, Shanghai 201203, Peoples R China
5.Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, Peoples R China
推荐引用方式
GB/T 7714		 Wang, Yu-xiang,Zhang, Xu,Ma, Qing-yang,et al. Adaptive resistance to PI3K alpha-selective inhibitor CYH33 is mediated by genomic and transcriptomic alterations in ESCC cells[J]. CELL DEATH & DISEASE,2021,12(1):13.
APA Wang, Yu-xiang.,Zhang, Xu.,Ma, Qing-yang.,Hu, Lan-dian.,Zhang, Xi.,...&Meng, Ling-hua.(2021).Adaptive resistance to PI3K alpha-selective inhibitor CYH33 is mediated by genomic and transcriptomic alterations in ESCC cells.CELL DEATH & DISEASE,12(1),13.
MLA Wang, Yu-xiang,et al."Adaptive resistance to PI3K alpha-selective inhibitor CYH33 is mediated by genomic and transcriptomic alterations in ESCC cells".CELL DEATH & DISEASE 12.1(2021):13.

入库方式： OAI收割

来源：上海药物研究所

浏览0
下载0
收藏0
其他版本

除非特别说明，本系统中所有内容都受版权保护，并保留所有权利。