Abstract:
Melanoma tumors exhibit a wide range of heterogeneity in genomics even with shared mutations in the MAPK pathway, including BRAF mutations. Consistently, adaptive drug resistance to BRAF inhibitors and/or BRAF plus 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. The PLXNC1 gene links the shared gene set and the enriched signature gene sets as it presented in all analysis results. As the PLXNC1 gene 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:
黑色素瘤肿瘤在基因组学中表现出广泛的异质性,即使在MAPK通路中存在共有突变,包括BRAF突变.始终如一,对BRAF抑制剂和/或BRAF加MEK抑制剂的适应性耐药性也表现出广泛的异质性反应,这对发现可用于临床克服耐药性的常见基因和途径构成了障碍。这项研究客观地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和BRAFi和/或MEKi抗性肿瘤。响应于BRAFi和BRAFi/MEKi的异质性是明显的,因为预处理的肿瘤和抗性肿瘤没有表现出聚集在一起的趋势。差异表达基因(DEG)分析揭示了两组数据共有的八个基因和两个相关的富集签名基因集(矩阵组和矩阵相关的签名基因集)。母系与肿瘤微环境和免疫反应密切相关,八个共有基因中的五个也与免疫反应有关。PLXNC1基因连接共享的基因集和富集的标记基因集,如在所有分析结果中呈现的。由于PLXNC1基因在耐药肿瘤中上调,我们在实验室中使用vemurafenib抗性细胞系验证了该基因的上调。鉴于其在促进炎症中的作用,这项研究表明,耐药肿瘤表现出炎性肿瘤微环境。这项研究中确定的矩阵组和特定的免疫基因集的参与可能为开发未来的治疗方法提供新的机会。