Adaptive resistance to PI3K alpha-selective inhibitor CYH33 is mediated by genomic and transcriptomic alterations in ESCC cells

doi:10.1038/s41419-020-03370-4

	Adaptive resistance to PI3K alpha-selective inhibitor CYH33 is mediated by genomic and transcriptomic alterations in ESCC cells
	Wang, Yu-xiang 2; Zhang, Xu 2,3; Ma, Qing-yang 4; Hu, Lan-dian 4; Zhang, Xi 2; Wang, Yi 2; Xu, Lan 2; Yang, Chun-hao 5; Tan, Cun 5; Kong, Xiang-yin 4
刊名	CELL DEATH & DISEASE
	2021-01-14
卷号	12 期号:1 页码:13
ISSN号	2041-4889
DOI	10.1038/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.
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关键词	SCREENING REVEALS ; LUNG-CANCER ; CARCINOMA ; MUTATION ; COMBINATION ; ACTIVATION ; LANDSCAPE ; MECHANISM ; KINASE ; POTENT
WOS研究方向	Cell Biology
语种	英语
出版者	SPRINGERNATURE
WOS记录号	WOS:000609814100003
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/295954]
专题	中国科学院上海药物研究所
通讯作者	Ding, Jian; Meng, Ling-hua
作者单位	1.Chinese Acad Sci, Shanghai Inst Mat Med, Div Antitumor Pharmacol, State Key Lab Drug Res, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China 2.Chinese Acad Sci, Shanghai Inst Mat Med, Div Antitumor Pharmacol, 501 Haike Rd, Shanghai 201203, Peoples R China 3.Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, Peoples R China 4.Chinese Acad Sci, Shanghai Inst Nutr & Hlth, 320 Yueyang Rd, Shanghai 200031, Peoples R China 5.Chinese Acad Sci, Shanghai Inst Mat Med, Dept Med Chem, 555 Zuchongzhi Rd, Shanghai 200120, 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.