Unraveling the CDK9/PP2A/ERK Network in Transcriptional Pause Release and Complement Activation in KRAS-mutant Cancers
文献类型：期刊论文
| 作者 | Wang, Yafang6; Xu, Lansong5,6; Ling, Lijun6; Yao, Mingyue4,5,6; Shi, Shangxuan3,6; Yu, Chengcheng2,4; Li, Yingnian4; Shen, Jie1; Jiang, Hualiang2,3,6 ; Xie, Chengying3,4,6
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| 刊名 | ADVANCED SCIENCE
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| 出版日期 | 2024-09-10 |
| 页码 | 20 |
| 关键词 | KRAS CDK9 ERK complement activation immunosuppression |
| DOI | 10.1002/advs.202404926 |
| 通讯作者 | Xie, Chengying(xiecy@lglab.ac.cn) |
| 英文摘要 | Selective inhibition of the transcription elongation factor (P-TEFb) complex represents a promising approach in cancer therapy, yet CDK9 inhibitors (CDK9i) are currently limited primarily to certain hematological malignancies. Herein, while initial responses to CDK9-targeted therapies are observed in vitro across various KRAS-mutant cancer types, their efficacy is far from satisfactory in nude mouse xenograft models. Mechanistically, CDK9 inhibition leads to compensatory activation of ERK-MYC signaling, accompanied by the recovery of proto-oncogenes, upregulation of immediate early genes (IEGs), stimulation of the complement C1r-C3-C3a cascade, and induction of tumor immunosuppression. The "paradoxical" regulation of PP2Ac activity involving the CDK9/Src interplay contributes to ERK phosphorylation and pause-release of RNA polymerase II (Pol II). Co-targeting of CDK9 and KRAS/MAPK signaling pathways eliminates ERK-MYC activation and prevents feedback activation mediated by receptor tyrosine kinases, leading to more effective control of KRAS-mutant cancers and overcoming KRASi resistance. Moreover, modulating the tumor microenvironment (TME) by complement system intervention enhances the response to CDK9i and potently suppresses tumor growth. Overall, the preclinical investigations establish a robust framework for conducting clinical trials employing KRASi/SOS1i/MEKi or immunomodifiers in combination with CDK9i to simultaneously target cancer cells and their crosstalk with the TME, thereby yielding improved responses in KRAS-mutant patients. This study reveals the CDK9/PP2A/ERK network involved in transcriptional pause release and complement activation in KRAS-mutant cancers, which limits the efficacy of CDK9i in vivo. The preclinical investigations establish a robust framework for conducting clinical trials employing KRASi/SOS1i/MEKi or immunomodifiers combined with CDK9i to simultaneously target cancer cells and their crosstalk with tumor microenvironment, thereby enhancing efficacy and overcoming resistance. image |
| WOS关键词 | II-DEPENDENT TRANSCRIPTION ; CELL-DEATH ; INHIBITION ; CDK9 ; TARGET ; PHOSPHORYLATION ; RESISTANCE ; GENES ; ERK |
| 资助项目 | Multi-Omics Facility of the School and Life Science and Technology ; Discovery Technology Platform of the Shanghai Institute for Advanced Immunochemical Studies at ShanghaiTech University[LG202101-01-06] ; ShanghaiTech University ; Shanghai Municipal Government |
| WOS研究方向 | Chemistry ; Science & Technology - Other Topics ; Materials Science |
| 语种 | 英语 |
| WOS记录号 | WOS:001308668400001 |
| 出版者 | WILEY |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/313302]  |
| 专题 | 中国科学院上海药物研究所 |
| 通讯作者 | Xie, Chengying |
| 作者单位 | 1.Shanghai Univ Tradit Chinese Med, Shuguang Hosp, Dept Pharm, SATCM Grade Lab Tradit Chinese Med Preparat 3, Shanghai 201203, Peoples R China 2.Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Dev Ctr, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China 3.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China 4.Lingang Lab, Shanghai 200031, Peoples R China 5.Univ Sci & Technol China, Affiliated Hosp 1, Anhui Prov Hosp, Div Life Sci & Med, Hefei 230026, Anhui, Peoples R China 6.ShanghaiTech Univ, Shanghai Inst Adv Immunochem Studies, 393 Middle Huaxia Rd, Shanghai 201210, Peoples R China |
| 推荐引用方式 GB/T 7714 | Wang, Yafang,Xu, Lansong,Ling, Lijun,et al. Unraveling the CDK9/PP2A/ERK Network in Transcriptional Pause Release and Complement Activation in KRAS-mutant Cancers[J]. ADVANCED SCIENCE,2024:20. |
| APA | Wang, Yafang.,Xu, Lansong.,Ling, Lijun.,Yao, Mingyue.,Shi, Shangxuan.,...&Xie, Chengying.(2024).Unraveling the CDK9/PP2A/ERK Network in Transcriptional Pause Release and Complement Activation in KRAS-mutant Cancers.ADVANCED SCIENCE,20. |
| MLA | Wang, Yafang,et al."Unraveling the CDK9/PP2A/ERK Network in Transcriptional Pause Release and Complement Activation in KRAS-mutant Cancers".ADVANCED SCIENCE (2024):20. |
入库方式： OAI收割
来源：上海药物研究所
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