Prognosis of triple-negative breast cancer (TNBC) remains poor. To identify shared and selective vulnerabilities of basal-like TNBC, the most common TNBC subtype, a directed siRNA lethality screen was performed in 7 human breast cancer cell lines, focusing on 154 previously identified dependency genes of 1 TNBC line. Thirty common dependency genes were identified, including multiple proteasome and RNA splicing genes, especially those associated with the U4/U6.U5 tri-snRNP complex (e.g., PRPF8, PRPF38A). PRPF8 or PRPF38A knockdown or the splicing modulator E7107 led to widespread intronic retention and altered splicing of transcripts involved in multiple basal-like TNBC dependencies, including protein homeostasis, mitosis, and apoptosis. E7107 treatment suppressed the growth of basal-A TNBC cell line and patient-derived basal-like TNBC xenografts at a well-tolerated dose. The antitumor response was enhanced by adding the proteasome inhibitor bortezomib. Thus, inhibiting both splicing and the proteasome might be an effective approach for treating basal-like TNBC. Mol Cancer Ther; 16(12); 2849–61. ©2017 AACR.

中文翻译：

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Basal-A 三阴性乳腺癌细胞选择性地依赖 RNA 剪接来生存


三阴性乳腺癌（TNBC）的预后仍然很差。为了确定基底样 TNBC（最常见的 TNBC 亚型）的共享和选择性脆弱性，在 7 个人类乳腺癌细胞系中进行了定向 siRNA 致死性筛选，重点关注 1 个 TNBC 细胞系的 154 个先前鉴定的依赖性基因。鉴定出 30 个常见依赖性基因，包括多种蛋白酶体和 RNA 剪接基因，特别是与 U4/U6.U5 tri-snRNP 复合物相关的基因（例如 PRPF8、PRPF38A）。 PRPF8 或 PRPF38A 敲低或剪接调节剂 E7107 导致广泛的内含子保留和转录物剪接改变，这些转录物涉及多种基础样 TNBC 依赖性，包括蛋白质稳态、有丝分裂和细胞凋亡。 E7107 治疗以耐受良好的剂量抑制了 basal-A TNBC 细胞系和患者来源的 basal 样 TNBC 异种移植物的生长。添加蛋白酶体抑制剂硼替佐米可增强抗肿瘤反应。因此，抑制剪接和蛋白酶体可能是治疗基底样 TNBC 的有效方法。摩尔癌症治疗； 16（12）； 2849–61。 ©2017 AACR。