CDK7 inhibition suppresses aberrant hedgehog pathway and overcomes resistance to smoothened antagonists

doi:10.1073/pnas.1815780116

	CDK7 inhibition suppresses aberrant hedgehog pathway and overcomes resistance to smoothened antagonists
	Liu, Fang 1; Jiang, Wenyan 1; Sui, Yi 1; Meng, Wei 2; Hou, Linjun3,4 ; Li, Tiantian 1; Li, Meng 1; Zhang, Lei 1; Mo, Jialin 1; Wang, Jiajia 2; Zhao, Yang 2; Zhang, Liye3 ; Ma, Jie 2; Tang, Yujie 1,2
	2019-06-25
发表期刊	PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA (IF:9.4[JCR-2023],10.8[5-Year])
ISSN	0027-8424
卷号	116 期号:26 页码:12986-12995
发表状态	已发表
DOI	10.1073/pnas.1815780116
摘要	The aberrant hedgehog (Hh) pathway plays important roles in multiple cancer types, therefore serving as a promising drug target. Current clinically available hedgehog-targeted drugs act mostly by antagonizing the upstream component smoothened; however, both primary and acquired resistance to FDA-approved smoothened inhibitor (SMOi) drugs have been described. We have recently demonstrated that the BET inhibitor effectively suppresses SMOi-resistant Hh-driven cancers through antagonizing transcription of GLI1 and GLI2, the core transcriptional factors of Hh pathway, suggesting epigenetic or transcriptional targeted therapy represents an anti-Hh therapeutic strategy that can overcome SMOi resistance. Here we performed an unbiased screening of epigenetic or transcriptional targeted small molecules to test their inhibitory effects on GLI1 and GLI2 transcription or cell viability of Hh-driven tumor lines. THZ1, a covalent inhibitor of cyclin-dependent kinase 7 (CDK7), is identified as the top hit in our screening. We then confirmed that antagonizing CDK7 by either small-molecule inhibitors or the CRISPR-Cas9 approach causes substantial suppression of GLI1 and GLI2 transcription, resulting in effective inhibition of Hh-driven cancers in vitro and in vivo. More importantly, antagonizing CDK7 retains inhibitory activity against Hh-driven cancers with almost all sofar described primary or acquired SMOi resistance. Furthermore, we reveal a synergy between CDK7 inhibition and BET inhibition on antagonizing aberrant Hh pathway and Hh-driven cancers that are either responsive or resistant to SMOi. Our results illustrate transcriptional inhibition through targeting CDK7 as a promising therapeutic strategy for treating Hh-driven cancers, especially those with primary or acquired resistance to SMOi drugs.
关键词	THZ1 CDK7 inhibition hedgehog pathway smoothened inhibitor medulloblastoma
收录类别	SCI ; SCIE
语种	英语
资助项目	Joint Research of Medicine and Industry of Shanghai Jiao Tong University[YG2015QN42]
WOS研究方向	Science & Technology - Other Topics
WOS类目	Multidisciplinary Sciences
WOS记录号	WOS:000472719100070
出版者	NATL ACAD SCIENCES
WOS关键词	ONCOGENIC TRANSCRIPTION ; PATCHED GENE ; MEDULLOBLASTOMA ; ACTIVATION ; MUTATIONS ; CANCER ; GROWTH ; SHH ; PROTEIN ; ASSOCIATION
原始文献类型	Article
引用统计	被引频次：21[WOS] [WOS记录] [WOS相关记录]
文献类型	期刊论文
条目标识符	https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/61087
专题	生命科学与技术学院_硕士生生命科学与技术学院_PI研究组_张力烨组
通讯作者	Ma, Jie; Tang, Yujie
作者单位	1.Shanghai Jiao Tong Univ, Sch Med, Key Lab Cell Differentiat & Apoptosis, Natl Minist Educ,Dept Pathophysiol, Shanghai 200025, Peoples R China 2.Shanghai Jiao Tong Univ, Sch Med, Dept Pediat Neurosurg, Xin Hua Hosp, Shanghai 200092, Peoples R China 3.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China 4.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
推荐引用方式 GB/T 7714	Liu, Fang,Jiang, Wenyan,Sui, Yi,et al. CDK7 inhibition suppresses aberrant hedgehog pathway and overcomes resistance to smoothened antagonists[J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA,2019,116(26):12986-12995.
APA	Liu, Fang.,Jiang, Wenyan.,Sui, Yi.,Meng, Wei.,Hou, Linjun.,...&Tang, Yujie.(2019).CDK7 inhibition suppresses aberrant hedgehog pathway and overcomes resistance to smoothened antagonists.PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA,116(26),12986-12995.
MLA	Liu, Fang,et al."CDK7 inhibition suppresses aberrant hedgehog pathway and overcomes resistance to smoothened antagonists".PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 116.26(2019):12986-12995.