Downregulation of c-Myc expression confers sensitivity to CHK1 inhibitors in hematologic malignancies

doi:10.1038/s41401-021-00652-1

	Downregulation of c-Myc expression confers sensitivity to CHK1 inhibitors in hematologic malignancies
	Jiang, Kai-long 1,2; Tong, Le-xian 3; Wang, Tao 4; Wang, Han-lin1,2,5 ; Hu, Xiao-bei 1,6; Xu, Gao-ya 1; Jin, Ting-ting 3; Kan, Wei-juan 1; Xu, Lei 1,2,6; Li, Jia-nan 1,7; Zhang, Kai-xiang 1,2; Song, Ning1,2,5 ; Liu, Jie-yu 1,2; Zhang, Meng-meng 1; Wu, Wen-biao 1,2; Xiang, Yu-qi1,2,5 ; Gao, An-hui 1; Hu, Yong-zhou 3; Zhou, Yu-bo 1,2,6; Liu, Tao 3; Yang, Jian-min 4; Li, Jia1,2,5,6
	2022-01
发表期刊	ACTA PHARMACOLOGICA SINICA
ISSN	1671-4083
EISSN	1745-7254
DOI	10.1038/s41401-021-00652-1
摘要	Checkpoint kinase 1 inhibitors (CHK1i) have shown impressive single-agent efficacy in treatment of certain tumors, as monotherapy or potentiators of chemotherapy in clinical trials, but the sensitive tumor types and downstream effectors to dictate the therapeutic responses to CHK1i remains unclear. In this study we first analyzed GDSC (Genomics of Drug Sensitivity in Cancer) and DepMap database and disclosed that hematologic malignancies (HMs) were relatively sensitive to CHK1i or CHK1 knockdown. This notion was confirmed by examining PY34, a new and potent in-house selective CHK1i, which exhibited potent anti-HM effect in vitro and in vivo, as single agent. We demonstrated that the downregulation of c-Myc and its signaling pathway was the common transcriptomic profiling response of sensitive HM cell lines to PY34, whereas overexpressing c-Myc could partially rescue the anticancer effect of PY34. Strikingly, we revealed the significant correlations between downregulation of c-Myc and cell sensitivity to PY34 in 17 HM cell lines and 39 patient-derived cell (PDC) samples. Thus, our results demonstrate that HMs are more sensitive to CHK1i than solid tumors, and c-Myc downregulation could represent the CHK1i efficacy in HMs.
关键词	CHK1 inhibitors PY34 drug sensitivity c-Myc hematologic malignancies
收录类别	SCIE
语种	英语
WOS研究方向	Chemistry ; Pharmacology & Pharmacy
WOS类目	Chemistry, Multidisciplinary ; Pharmacology & Pharmacy
WOS记录号	WOS:000634685300002
出版者	NATURE PUBLISHING GROUP
引用统计
文献类型	期刊论文
条目标识符	https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/126151
专题	生命科学与技术学院_博士生生命科学与技术学院_特聘教授组_李佳组生命科学与技术学院_硕士生
通讯作者	Li, Jia-nan; Zhou, Yu-bo; Liu, Tao; Yang, Jian-min
作者单位	1.Chinese Acad Sci, Shanghai Inst Mat Med, Natl Ctr Drug Screening, State Key Lab Drug Res, Shanghai 201203, Peoples R China; 2.Univ Chinese Acad Sci, Beijing 100049, Peoples R China; 3.Zhejiang Univ, Coll Pharmaceut Sci, ZJU ENS Joint Lab Med Chem, Zhejiang Prov Key Lab Anti Canc Drug Res, Hangzhou 310058, Peoples R China; 4.Naval Med Univ, Changhai Hosp, Shanghai 200433, Peoples R China; 5.Shanghai Tech Univ, Shanghai 201210, Peoples R China; 6.Chinese Acad Sci, Zhongshan Inst Drug Discovery, Inst Drug Discovery & Dev, Zhongshan 528400, Peoples R China; 7.Nanjing Univ Chinese Med, Coll Pharm, Nanjing 210033, Peoples R China
推荐引用方式 GB/T 7714	Jiang, Kai-long,Tong, Le-xian,Wang, Tao,et al. Downregulation of c-Myc expression confers sensitivity to CHK1 inhibitors in hematologic malignancies[J]. ACTA PHARMACOLOGICA SINICA,2022.
APA	Jiang, Kai-long.,Tong, Le-xian.,Wang, Tao.,Wang, Han-lin.,Hu, Xiao-bei.,...&Li, Jia.(2022).Downregulation of c-Myc expression confers sensitivity to CHK1 inhibitors in hematologic malignancies.ACTA PHARMACOLOGICA SINICA.
MLA	Jiang, Kai-long,et al."Downregulation of c-Myc expression confers sensitivity to CHK1 inhibitors in hematologic malignancies".ACTA PHARMACOLOGICA SINICA (2022).