Department of Clinical Laboratory, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China.
Department of Clinical Laboratory, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, Sichuan, China.
Sci Rep. 2023 Apr 12;13(1):5984. doi: 10.1038/s41598-023-32757-4.
Taking NVP-BEZ235 (BEZ235) as an example to screen drug response-related genes (DRRGs) and explore their potential value in triple-negative breast cancer (TNBC). Through high-throughput technique, multidimensional transcriptome expression data (mRNA, miRNA and lncRNA) of BEZ235-treated and -untreated MDA-MB-468 cell lines were obtained. Combined with transcriptome data of the MDA-MB-468 cells and TCGA-TNBC tissues, differential gene expression analysis and WGCNA were performed to identify DRRGs associated with tumor trait by simulating the drug response microenvironment (DRM) of BEZ235-treated patients. Based on DRRGs, we constructed a ceRNA network and verified the expression levels of three key molecules by RT-qPCR, which not only demonstrated the successful construction of a BEZ235-treated cell line model but also explained the antitumor mechanism of BEZ235. Four molecular subtypes related to the DRM with survival difference were proposed using cluster analysis, namely glycolysis subtype, proliferation depression subtype, immune-suppressed subtype, and immune-activated subtype. A novel prognostic signature consisting of four DRRGs was established by Lasso-Cox analysis, which exhibited outstanding performance in predicting overall survival compared with several excellent reported signatures. The high- and low-risk groups were characterized by enrichment of metabolism-related pathways and immune-related pathways, respectively. Of note, the low-risk group had a better response to immune checkpoint blockade. Besides, pRRophetic analysis found that patients in the low-risk group were more sensitive to methotrexate and cisplation, whereas more resistant to BEZ235, docetaxel and paclitaxel. In conclusion, the DRRGs exemplified by BEZ235 are potential biomarkers for TNBC molecular typing, prognosis prediction and targeted therapy. The novel DRRGs-guided strategy for predicting the subtype, survival and therapy efficacy, might be also applied to more cancers and drugs other than TNBC and BEZ235.
以 NVP-BEZ235（BEZ235）为例筛选药物反应相关基因（DRRGs），并探讨其在三阴性乳腺癌（TNBC）中的潜在价值。通过高通量技术，获得 BEZ235 处理和未处理 MDA-MB-468 细胞系的多维转录组表达数据（mRNA、miRNA 和 lncRNA）。结合 MDA-MB-468 细胞和 TCGA-TNBC 组织的转录组数据，通过模拟 BEZ235 处理患者的药物反应微环境（DRM），进行差异基因表达分析和 WGCNA，以识别与肿瘤特征相关的 DRRGs。基于 DRRGs，构建 ceRNA 网络，并通过 RT-qPCR 验证三个关键分子的表达水平，不仅成功构建了 BEZ235 处理细胞系模型，还解释了 BEZ235 的抗肿瘤机制。通过聚类分析提出了四种与 DRM 相关且具有生存差异的分子亚型，即糖酵解亚型、增殖抑制亚型、免疫抑制亚型和免疫激活亚型。通过 Lasso-Cox 分析建立了一个由四个 DRRGs 组成的新的预后签名，与几个优秀的报道签名相比，该签名在预测总生存期方面表现出色。高风险和低风险组的特征分别是代谢相关途径和免疫相关途径的富集。值得注意的是，低风险组对免疫检查点阻断的反应更好。此外，pRRophetic 分析发现，低风险组的患者对甲氨蝶呤和顺铂更敏感，而对 BEZ235、多西他赛和紫杉醇更耐药。总之，以 BEZ235 为代表的 DRRGs 是 TNBC 分子分型、预后预测和靶向治疗的潜在生物标志物。新的 DRRGs 指导的预测亚型、生存和治疗效果的策略，也可能适用于除 TNBC 和 BEZ235 之外的更多癌症和药物。
