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.
Cell Chem Biol. 2024 Nov 21;31(11):1942-1957.e6. doi: 10.1016/j.chembiol.2024.08.003. Epub 2024 Sep 3.
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.
紫杉醇耐药三阴性乳腺癌（TNBC）仍然是治疗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，发现紫杉醇耐药 TNBC 细胞对蛋白质精氨酸甲基转移酶（PRMTs）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的杀伤。PRMT5 的遗传或药理学抑制会改变 RNA 剪接，特别是 Aurora 激酶 B（AURKB）的内含子保留，导致蛋白表达减少，最终导致紫杉醇耐药细胞中选择性有丝分裂灾难。此外，I 型 PRMT 抑制通过增强 AURKB 介导的有丝分裂信号通路的干扰，与 PRMT5 抑制协同抑制耐药细胞的肿瘤生长。这些发现完全在从紫杉醇耐药 TNBC 患者中生成的患者来源异种移植（PDX）模型中得到了重现，为在紫杉醇耐药 TNBC 中靶向 PRMTs 提供了依据。
