文章：

无监督分析揭示关键免疫应答基因与基质组在黑色素瘤对BRAF及MEK抑制剂耐药机制中的核心作用

Unsupervised Analysis Reveals the Involvement of Key Immune Response Genes and the Matrisome in Resistance to BRAF and MEK Inhibitors in Melanoma

原文发布日期：24 June 2024

DOI: 10.3390/cancers16132313

类型: Article

开放获取: 是

英文摘要：

Melanoma tumors exhibit a wide range of heterogeneity in genomics even with shared mutations in the MAPK pathway, includingBRAFmutations. Consistently, adaptive drug resistance toBRAFinhibitors and/orBRAFplus MEK inhibitors also exhibits a wide range of heterogeneous responses, which poses an obstacle for discovering common genes and pathways that can be used in clinic for overcoming drug resistance. This study objectively analyzed two sets of previously published tumor genomics data comparing pre-treated melanoma tumors and BRAFi- and/or MEKi-resistant tumors. Heterogeneity in response to BRAFi and BRAFi/MEKi was evident because the pre-treated tumors and resistant tumors did not exhibit a tendency of clustering together. Differentially expressed gene (DEG) analysis revealed eight genes and two related enriched signature gene sets (matrisome and matrisome-associated signature gene sets) shared by both sets of data. The matrisome was closely related to the tumor microenvironment and immune response, and five out of the eight shared genes were also related to immune response. ThePLXNC1gene links the shared gene set and the enriched signature gene sets as it presented in all analysis results. As thePLXNC1gene was up-regulated in the resistant tumors, we validated the up-regulation of this gene in a laboratory using vemurafenib-resistant cell lines. Given its role in promoting inflammation, this study suggests that resistant tumors exhibit an inflammatory tumor microenvironment. The involvement of the matrisome and the specific set of immune genes identified in this study may provide new opportunities for developing future therapeutic methods.

摘要翻译： 

黑色素瘤肿瘤在基因组学上表现出广泛的异质性，即使存在MAPK通路（包括BRAF突变）的共享突变。相应地，对BRAF抑制剂和/或BRAF联合MEK抑制剂的适应性耐药也呈现出广泛的异质性反应，这为发现可用于临床克服耐药的共同基因和通路带来了障碍。本研究客观分析了两组先前发表的肿瘤基因组学数据，比较了治疗前的黑色素瘤肿瘤与BRAFi和/或MEKi耐药肿瘤。对BRAFi和BRAFi/MEKi反应的异质性显而易见，因为治疗前肿瘤和耐药肿瘤并未表现出聚集在一起的趋势。差异表达基因（DEG）分析揭示了八种基因和两个相关的富集特征基因集（基质组和基质组相关特征基因集），这些在两组数据中均共享。基质组与肿瘤微环境和免疫反应密切相关，而八种共享基因中有五种也与免疫反应相关。PLXNC1基因作为共享基因集与富集特征基因集之间的桥梁，出现在所有分析结果中。由于PLXNC1基因在耐药肿瘤中表达上调，我们使用维莫非尼耐药细胞系在实验室中验证了该基因的上调。鉴于其在促进炎症中的作用，本研究提示耐药肿瘤表现出炎症性肿瘤微环境。本研究中发现的基质组及特定免疫基因集的参与，可能为开发未来治疗方法提供新的机遇。

原文链接：

Unsupervised Analysis Reveals the Involvement of Key Immune Response Genes and the Matrisome in Resistance to BRAF and MEK Inhibitors in Melanoma