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

IF 6.6 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Cell Chemical Biology Pub Date : 2024-09-03 DOI:10.1016/j.chembiol.2024.08.003

KeJing Zhang, Juan Wei, SheYu Zhang, Liyan Fei, Lu Guo, Xueying Liu, YiShuai Ji, WenJun Chen, Felipe E. Ciamponi, WeiChang Chen, MengXi Li, Jie Zhai, Ting Fu, Katlin B. Massirer, Yang Yu, Mathieu Lupien, Yong Wei, Cheryl. H. Arrowsmith, Qin Wu, WeiHong Tan

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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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化学筛选发现 PRMT5 是紫杉醇耐药三阴性乳腺癌的治疗漏洞

紫杉醇耐药的三阴性乳腺癌（TNBC）仍然是最难治疗的乳腺癌之一。在这里，我们利用表观遗传化学探针筛选，发现了耐紫杉醇的 TNBC 细胞对蛋白精氨酸甲基转移酶（PRMTs）抑制的后天脆弱性。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的杀伤。遗传或药物抑制 PRMT5 会改变 RNA 剪接，特别是极光激酶 B（AURKB）的内含子保留，导致蛋白质表达减少，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，通过增强对AURKB介导的有丝分裂信号通路的干扰，抑制耐药细胞的肿瘤生长。这些发现在由紫杉醇耐药的 TNBC 患者生成的患者衍生异种移植（PDX）模型中得到了充分再现，为在紫杉醇耐药的 TNBC 中靶向 PRMTs 提供了理论依据。

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来源期刊

Cell Chemical Biology Biochemistry, Genetics and Molecular Biology-Molecular Medicine

CiteScore

14.70

自引率

2.30%

发文量

143

期刊介绍： Cell Chemical Biology, a Cell Press journal established in 1994 as Chemistry & Biology, focuses on publishing crucial advances in chemical biology research with broad appeal to our diverse community, spanning basic scientists to clinicians. Pioneering investigations at the chemistry-biology interface, the journal fosters collaboration between these disciplines. We encourage submissions providing significant conceptual advancements of broad interest across chemical, biological, clinical, and related fields. Particularly sought are articles utilizing chemical tools to perturb, visualize, and measure biological systems, offering unique insights into molecular mechanisms, disease biology, and therapeutics.