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P300/CBP inhibition sensitizes mantle cell lymphoma to PI3K delta inhibitor idelalisib

文献类型：期刊论文

作者Zhou, Xiao-ru2,3,6; Li, Xiao2,6; Liao, Li-ping2,6; Han, Jie6; Huang, Jing2,6; Li, Jia-cheng2,6; Tao, Hong-ru2,6; Fan, Shi-jie2,6; Chen, Zhi-feng6; Li, Qi6
刊名ACTA PHARMACOLOGICA SINICA
出版日期2021-04-13
页码13
ISSN号1671-4083
关键词mantle cell lymphoma idelalisib drug resistance P300 CBP synergistic drug action PI3Kδ epigenetics
DOI10.1038/s41401-021-00643-2
通讯作者Zhang, Yuan-yuan(Zhangyy@simm.ac.cn) ; Huang, Chuan-xin(huangcx@shsmu.edu.cn) ; Luo, Cheng(cluo@simm.ac.cn)
英文摘要Mantle cell lymphoma (MCL) is a lymphoproliferative disorder lacking reliable therapies. PI3K pathway contributes to the pathogenesis of MCL, serving as a potential target. However, idelalisib, an FDA-approved drug targeting PI3K delta, has shown intrinsic resistance in MCL treatment. Here we report that a p300/CBP inhibitor, A-485, could overcome resistance to idelalisib in MCL cells in vitro and in vivo. A-485 was discovered in a combinational drug screening from an epigenetic compound library containing 45 small molecule modulators. We found that A-485, the highly selective catalytic inhibitor of p300 and CBP, was the most potent compound that enhanced the sensitivity of MCL cell line Z-138 to idelalisib. Combination of A-485 and idelalisib remarkably decreased the viability of three MCL cell lines tested. Co-treatment with A-485 and idelalisib in Maver-1 and Z-138 MCL cell xenograft mice for 3 weeks dramatically suppressed the tumor growth by reversing the unsustained inhibition in PI3K downstream signaling. We further demonstrated that p300/CBP inhibition decreased histone acetylation at RTKs gene promoters and reduced transcriptional upregulation of RTKs, thereby inhibiting the downstream persistent activation of MAPK/ERK signaling, which also contributed to the pathogenesis of MCL. Therefore, additional inhibition of p300/CBP blocked MAPK/ERK signaling, which rendered maintaining activation to PI3K-mTOR downstream signals p-S6 and p-4E-BP1, thus leading to suppression of cell growth and tumor progression and eliminating the intrinsic resistance to idelalisib ultimately. Our results provide a promising combination therapy for MCL and highlight the potential use of epigenetic inhibitors targeting p300/CBP to reverse drug resistance in tumor.
资助项目National Natural Science Foundation of China[81625022] ; National Natural Science Foundation of China[91853205] ; National Natural Science Foundation of China[81821005] ; National Natural Science Foundation of China[81803554] ; National Natural Science Foundation of China[81703415] ; National Natural Science Foundation of China[81973166] ; National Natural Science Foundation of China[21820102008] ; Chinese Academy of Science grant[XDA12020353] ; KC Wong Education Foundation ; National Science and Technology Major Project[2018ZX09711002-008-005] ; National Science and Technology Major Project[2018ZX09711002] ; Science and Technology Commission of Shanghai Municipality[18431907100] ; Science and Technology Commission of Shanghai Municipality[19XD1404700] ; Youth Innovation Promotion Association[2017333]
WOS研究方向Chemistry ; Pharmacology & Pharmacy
语种英语
出版者NATURE PUBLISHING GROUP
WOS记录号WOS:000639768200001
源URL[http://119.78.100.183/handle/2S10ELR8/296572]  
专题新药研究国家重点实验室
通讯作者Zhang, Yuan-yuan; Huang, Chuan-xin; Luo, Cheng
作者单位1.Shanghai Jiao Tong Univ, Key Lab Cell Differentiat & Apoptosis, Dept Immunol & Microbiol, Chinese Minist Educ,Fac Basic Med,Sch Med, Shanghai 200025, Peoples R China
2.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
3.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 200031, Peoples R China
4.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Dept Med Chem, Shanghai 201203, Peoples R China
5.Shanghai Jiao Tong Univ, Key Lab Cell Differentiat & Apoptosis, Shanghai Inst Immunol, Chinese Minist Educ,Fac Basic Med,Sch Med, Shanghai 200025, Peoples R China
6.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Drug Discovery & Design Ctr,Ctr Chem Biol, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 Zhou, Xiao-ru,Li, Xiao,Liao, Li-ping,et al. P300/CBP inhibition sensitizes mantle cell lymphoma to PI3K delta inhibitor idelalisib[J]. ACTA PHARMACOLOGICA SINICA,2021:13.
APA Zhou, Xiao-ru.,Li, Xiao.,Liao, Li-ping.,Han, Jie.,Huang, Jing.,...&Luo, Cheng.(2021).P300/CBP inhibition sensitizes mantle cell lymphoma to PI3K delta inhibitor idelalisib.ACTA PHARMACOLOGICA SINICA,13.
MLA Zhou, Xiao-ru,et al."P300/CBP inhibition sensitizes mantle cell lymphoma to PI3K delta inhibitor idelalisib".ACTA PHARMACOLOGICA SINICA (2021):13.

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来源：上海药物研究所

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