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A chemical screen identifies PRMT5 as a therapeutic vulnerability for paclitaxel-resistant triple-negative breast cancer.
Zhang, KeJing; Wei, Juan; Zhang, SheYu; Fei, Liyan; Guo, Lu; Liu, Xueying; Ji, YiShuai; Chen, WenJun; Ciamponi, Felipe E; Chen, WeiChang; Li, MengXi; Zhai, Jie; Fu, Ting; Massirer, Katlin B; Yu, Yang; Lupien, Mathieu; Wei, Yong; Arrowsmith, Cheryl H; Wu, Qin; Tan, WeiHong.
Afiliação
  • Zhang K; Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou 310018, China; Department of General Surgery, Xiangya Hospital, Central South University, Changsha, Hunan 410083, China; Clinical Research Center for Breast Cancer in Hunan Province, Changsha, Hunan
  • Wei J; Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou 310018, China.
  • Zhang S; Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou 310018, China; School of Pharmaceutical Science and Technology, Tianjin University, Tianjin 300072, China.
  • Fei L; Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou 310018, China.
  • Guo L; Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou 310018, China.
  • Liu X; Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou 310018, China.
  • Ji Y; Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou 310018, China; School of Pharmaceutical Science and Technology, Tianjin University, Tianjin 300072, China.
  • Chen W; Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou 310018, China.
  • Ciamponi FE; Molecular Biology and Genetic Engineering Center (CBMEG), Medicinal Chemistry Center (CQMED), Structural Genomics Consortium (SGC-UNICAMP), University of Campinas-UNICAMP, Campinas 13083-872, Brazil.
  • Chen W; Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou 310018, China.
  • Li M; Department of General Surgery, Xiangya Hospital, Central South University, Changsha, Hunan 410083, China; Clinical Research Center for Breast Cancer in Hunan Province, Changsha, Hunan 410000, China.
  • Zhai J; Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou 310018, China.
  • Fu T; Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou 310018, China.
  • Massirer KB; Molecular Biology and Genetic Engineering Center (CBMEG), Medicinal Chemistry Center (CQMED), Structural Genomics Consortium (SGC-UNICAMP), University of Campinas-UNICAMP, Campinas 13083-872, Brazil.
  • Yu Y; Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou 310018, China.
  • Lupien M; Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5S 1A1, Canada; Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario M5G 2C4, Canada; Ontario Institute for Cancer Research, Toronto, Ontario M5G 0A3, Canada.
  • Wei Y; Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou 310018, China. Electronic address: weiyong@ibmc.ac.cn.
  • Arrowsmith CH; Structural Genomics Consortium, University of Toronto, Toronto, Ontario M5S 1A1, Canada; Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5S 1A1, Canada; Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario M5G 2C4, Canada. Electronic address: cheryl
  • Wu Q; Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou 310018, China. Electronic address: wuqin@ibmc.ac.cn.
  • Tan W; Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou 310018, China. Electronic address: tan@hnu.edu.cn.
Cell Chem Biol ; 2024 Aug 21.
Article em En | MEDLINE | ID: mdl-39232499
ABSTRACT
Paclitaxel-resistant triple negative breast cancer (TNBC) remains one of the most challenging breast cancers to treat. Here, using an epigenetic chemical probe screen, we uncover an acquired vulnerability of paclitaxel-resistant TNBC cells to protein arginine methyltransferases (PRMTs) inhibition. Analysis of cell lines and in-house clinical samples demonstrates that resistant cells evade paclitaxel killing through stabilizing mitotic chromatin assembly. Genetic or pharmacologic inhibition of PRMT5 alters RNA splicing, particularly intron retention of aurora kinases B (AURKB), leading to a decrease in protein expression, and finally results in selective mitosis catastrophe in paclitaxel-resistant cells. In addition, type I PRMT inhibition synergies with PRMT5 inhibition in suppressing tumor growth of drug-resistant cells through augmenting perturbation of AURKB-mediated mitotic signaling pathway. These findings are fully recapitulated in a patient-derived xenograft (PDX) model generated from a paclitaxel-resistant TNBC patient, providing the rationale for targeting PRMTs in paclitaxel-resistant TNBC.
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Texto completo: 1 Base de dados: MEDLINE Idioma: En Ano de publicação: 2024 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Idioma: En Ano de publicação: 2024 Tipo de documento: Article