College of Pharmacy, Sookmyung Women's University, Seoul 04310, Republic of Korea.
School of Pharmacy, Sungkyunkwan University, Suwon 16419, Republic of Korea.
Genes (Basel). 2024 Jul 22;15(7):959. doi: 10.3390/genes15070959.
Poly(ADP-ribose) polymerase (PARP) inhibitors are targeted therapies that accumulate DNA damage by interfering with DNA repair mechanisms and are approved for treating several cancers with BRCA1/2 mutations. In this study, we utilized CRISPR-dCas9 interference screening to identify genes regulating sensitivity to PARP inhibitors in breast cancer cell lines. Our findings indicated that the interferon (IFN) signaling gene IRF9 was critically involved in modulating sensitivity to these inhibitors. We revealed that the loss of IRF9 leads to increased resistance to the PARP inhibitor in MDA-MB-468 cells, and a similar desensitization was observed in another breast cancer cell line, MDA-MB-231. Further analysis indicated that while the basal expression of IRF9 did not correlate with the response to the PARP inhibitor olaparib, its transcriptional induction was significantly associated with increased sensitivity to the DNA-damaging agent cisplatin in the NCI-60 cell line panel. This finding suggests a mechanistic link between IRF9 induction and cellular responses to DNA damage. Additionally, data from the METABRIC patient tissue study revealed a complex network of IFN-responsive gene expressions postchemotherapy, with seven upregulated genes, including IRF9, and three downregulated genes. These findings underscore the intricate role of IFN signaling in the cellular response to chemotherapy. Collectively, our CRISPR screening data and subsequent bioinformatic analyses suggest that IRF9 is a novel biomarker for sensitivity to DNA-damaging agents, such as olaparib and platinum-based chemotherapeutic agents. Our findings for IRF9 not only enhance our understanding of the genetic basis of drug sensitivity, but also elucidate the role of IRF9 as a critical effector within IFN signaling pathways, potentially influencing the association between the host immune system and chemotherapeutic efficacy.
聚（ADP-核糖）聚合酶（PARP）抑制剂是通过干扰 DNA 修复机制来累积 DNA 损伤的靶向治疗药物，已被批准用于治疗具有 BRCA1/2 突变的几种癌症。在这项研究中，我们利用 CRISPR-dCas9 干扰筛选来鉴定调节乳腺癌细胞系对 PARP 抑制剂敏感性的基因。我们的研究结果表明，干扰素（IFN）信号基因 IRF9 对于调节这些抑制剂的敏感性至关重要。我们揭示了 IRF9 的缺失会导致 MDA-MB-468 细胞对 PARP 抑制剂的耐药性增加，并且在另一种乳腺癌细胞系 MDA-MB-231 中也观察到类似的脱敏作用。进一步的分析表明，虽然 IRF9 的基础表达与对 PARP 抑制剂奥拉帕利的反应无关，但它的转录诱导与 NCI-60 细胞系面板中对 DNA 损伤剂顺铂的敏感性增加显著相关。这一发现表明了 IRF9 诱导与细胞对 DNA 损伤的反应之间的机制联系。此外，来自 METABRIC 患者组织研究的数据显示，化疗后 IFN 反应基因表达存在复杂的网络，其中有七个上调基因，包括 IRF9，还有三个下调基因。这些发现强调了 IFN 信号在细胞对化疗的反应中的复杂作用。总的来说，我们的 CRISPR 筛选数据和随后的生物信息学分析表明，IRF9 是对 DNA 损伤剂（如奥拉帕利和铂类化疗药物）敏感的新型生物标志物。我们对 IRF9 的发现不仅增强了我们对药物敏感性遗传基础的理解，还阐明了 IRF9 作为 IFN 信号通路中的关键效应因子的作用，可能影响宿主免疫系统与化疗疗效之间的关联。
