文章：

CRISPR-Cas9全基因组及双基因敲除筛选鉴定三阴性乳腺癌化疗耐药新治疗靶点

CRISPR-Cas9 Genome and Double-Knockout Screening to Identify Novel Therapeutic Targets for Chemoresistance in Triple-Negative Breast Cancer

原文发布日期：3 December 2025

DOI: 10.3390/cancers17233876

类型: Article

开放获取: 是

英文摘要：

Background/Objectives: Triple-negative breast cancer (TNBC) accounts for 15 to 20% of breast cancer cases and contributes to a disproportionate 35% of breast cancer deaths. Its resistance to chemotherapy presents a significant challenge.Methods: We firstly compared transcriptomic profiles between TNBC cell lines and patient samples and inferred the MDA-MB-231 cell line as the most representative model for TNBC with poor response to chemotherapy. We then conducted a genome-wide CRISPR-Cas9 screening and RNA-seq analysis in MDA-MB-231.Results: This analysis revealed 96 and 93 genes that could re-sensitize cisplatin and doxorubicin treatment, respectively, with 19 overlapping genes. Among these genes, 28 have been studied and published previously in chemoresistance research. MCM9 was found as a new TNBC chemoresistance target. Its target drug, KPT-185, showed an additive effect with cisplatin in treating TNBC cells. In the follow-up gene combination double-knockout experiment among 65 genes selected from cell death pathways, 242 synthetic lethal gene pairs were discovered to overcome chemoresistance in TNBC.Conclusions: In this study, we identified synthetic lethal targets in treating TNBC with cisplatin and doxorubicin through a genome-wide CRISPR-Cas9 screening and gene combination double-knockout screening.

摘要翻译： 

背景/目的：三阴性乳腺癌（TNBC）占乳腺癌病例的15%至20%，却导致了高达35%的乳腺癌死亡，比例显著失衡。其对化疗的耐药性构成了重大挑战。 方法：我们首先比较了TNBC细胞系与患者样本的转录组谱，推断MDA-MB-231细胞系是对化疗反应不佳的TNBC最具代表性的模型。随后，我们在MDA-MB-231细胞中进行了全基因组CRISPR-Cas9筛选和RNA-seq分析。 结果：分析揭示了分别有96个和93个基因能够重新敏化顺铂和阿霉素的治疗效果，其中19个基因重叠。在这些基因中，已有28个在化疗耐药性研究中被报道。MCM9被发现是一个新的TNBC化疗耐药靶点。其靶向药物KPT-185在治疗TNBC细胞时与顺铂显示出协同效应。在从细胞死亡通路中选出的65个基因进行的后续基因组合双敲除实验中，发现了242对合成致死基因对，可用于克服TNBC的化疗耐药性。 结论：本研究通过全基因组CRISPR-Cas9筛选和基因组合双敲除筛选，确定了在顺铂和阿霉素治疗TNBC中的合成致死靶点。

原文链接：

CRISPR-Cas9 Genome and Double-Knockout Screening to Identify Novel Therapeutic Targets for Chemoresistance in Triple-Negative Breast Cancer