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.

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之一。在这里，我们使用表观遗传化学探针筛选，发现了紫杉醇耐药 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。 PRMT5 的遗传或药理学抑制会改变 RNA 剪接，特别是极光激酶 B (AURKB) 的内含子保留，导致蛋白质表达减少，最终导致紫杉醇抗性细胞中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。这些发现在由紫杉醇耐药 TNBC 患者生成的患者来源异种移植 (PDX) 模型中得到了充分概括，为在紫杉醇耐药 TNBC 中靶向 PRMT 提供了基本原理。