A chemical screen identifies PRMT5 as a therapeutic vulnerability for paclitaxel-resistant triple-negative breast cancer,Cell Chemical Biology

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A chemical screen identifies PRMT5 as a therapeutic vulnerability for paclitaxel-resistant triple-negative breast cancer
Cell Chemical Biology ( IF 6.6 ) Pub Date : 2024-09-03 , DOI: 10.1016/j.chembiol.2024.08.003
KeJing Zhang ₁ , Juan Wei ₂ , SheYu Zhang ₃ , Liyan Fei ₂ , Lu Guo ₂ , Xueying Liu ₂ , YiShuai Ji ₃ , WenJun Chen ₂ , Felipe E Ciamponi ₄ , WeiChang Chen ₂ , MengXi Li ₅ , Jie Zhai ₂ , Ting Fu ₂ , Katlin B Massirer ₄ , Yang Yu ₂ , Mathieu Lupien ₆ , Yong Wei ₂ , Cheryl H Arrowsmith ₇ , Qin Wu ₂ , WeiHong Tan ₂

Affiliation

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 410000, China.
Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou 310018, China.
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.
Molecular Biology and Genetic Engineering Center (CBMEG), Medicinal Chemistry Center (CQMED), Structural Genomics Consortium (SGC-UNICAMP), University of Campinas-UNICAMP, Campinas 13083-872, Brazil.
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.
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.
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.

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.

中文翻译：

化学筛选确定 PRMT5 是紫杉醇耐药三阴性乳腺癌的治疗脆弱性

紫杉醇耐药的三阴性乳腺癌（TNBC）仍然是最具挑战性的乳腺癌治疗之一。在这里，使用表观遗传学探针筛选，我们揭示了紫杉醇耐药 TNBC 细胞对蛋白质精氨酸甲基转移酶（PRMT）抑制的获得性脆弱性。对细胞系和内部临床样本的分析表明，耐药细胞通过稳定有丝分裂染色质组装来逃避紫杉醇杀伤。PRMT5 的遗传或药物抑制会改变 RNA 剪接，特别是极光激酶 B （AURKB）的内含子保留，导致蛋白质表达降低，并最终导致紫杉醇耐药细胞的选择性有丝分裂灾难。此外，I 型 PRMT 抑制与 PRMT5 抑制协同作用，通过增强 AURKB 介导的有丝分裂信号通路的扰动来抑制耐药细胞的肿瘤生长。这些发现完全概括在由紫杉醇耐药 TNBC 患者生成的患者来源的异种移植物（PDX）模型中，为在紫杉醇耐药 TNBC 中靶向 PRMT 提供了理论依据。

更新日期：2024-09-03

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