BRAF(V600E)黑色素瘤耐药的组蛋白重建规律及机制

Melanoma originates from the malignant transformation of melanocytes in the basal layer of the epidermis and is a highly aggressive skin cancer. BRAF is one of the most common mutant oncogenes. More than 80% of BRAF mutations in melanoma are BRAFV600E. Although BRAFV600E kinase inhibitor may prolong the survival of BRAFV600E melanoma patients to some extent, its efficacy is limited by the rapid generation of acquired resistance. The mechanisms of acquired BRAFi resistance such as reactivation of MAPK and PI3K/AKT signaling pathway have been elucidated. However, the role of epigenetic mechanisms represented by chromatin remodeling in drug resistance remains unclear. In this study, we will focus on the mechanisms by which the TrxG family of epigenetic regulators and other histone methylases regulate histone remodeling in BRAFV600E-resistant melanoma and their pivotal role in restoring the sensitivity of BRAF-targeted inhibitors. We aim to explore the epigenetic characteristics of drug resistance in BRAFV600E mutant melanoma, analyze the network of key drug resistance genes and its effect on tumor immune microenvironment, and restore the drug sensitivity by modifying histone modification. We will try to provide a solution of BRAFi resistance in BRAFV600E melanoma from a new perspective.

黑色素瘤起源于表皮基底层黑色素细胞的恶性转化，是一种具有高度侵袭性的皮肤癌。BRAF是最常见的突变致癌基因之一，在黑色素瘤中80%以上的BRAF突变为BRAFV600E。尽管BRAFV600E激酶抑制剂可在一定程度上延长BRAFV600E黑色素瘤病人的生存期，但由于获得性耐药的快速产生而限制其疗效。MAPK和PI3K/AKT信号通路的再激活等耐药机制已被阐明，而以染色质重塑为代表的表观遗传学机制在耐药中的作用仍不明确。本研究主要聚焦表观调控因子TrxG家族及其他组蛋白甲基化酶调控BRAFV600E黑色素瘤耐药的组蛋白重塑机制及其在恢复BRAF靶向抑制剂敏感性中的关键生物学作用，将从染色质重塑角度探讨BRAFV600E突变黑色素瘤耐药的表观遗传学特性，解析关键耐药基因网络及其对肿瘤免疫微环境的影响，通过改变组蛋白修饰恢复其药物敏感性，为解决BRAFV600E突变黑色素瘤的耐药提供新的思路。

黑色素瘤起源于表皮基底层黑色素细胞的恶性转化，是一种具有高度侵袭性的皮肤癌，BRAF是其最常见的突变致癌基因之一。在黑色素瘤中，80%以上的BRAF突变为BRAFV600E。尽管BRAFV600E激酶抑制剂可在一定程度上延长BRAFV600E黑色素瘤病人的生存期，但由于获得性耐药的快速产生而限制其疗效。本研究构建了对BRAFV600E激酶抑制剂dabrafenib耐药的黑色素瘤细胞株A375-DR，证明耐药后黑色素瘤的MAPK、PI3K/AKT通路活性增强、细胞迁移侵袭能力增强，且均不受dabrafenib影响；已耐药黑色素瘤的耐药表型在较长时间内不可逆转且影响MAPK通路其他靶向抑制剂的疗效；通过表观小分子化合物库筛选发现BRD4靶向抑制剂JQ1可显著抑制dabrafenib耐药黑色素瘤的增殖和迁移功能；证实了BRD4在染色体上的结合状态影响细胞对药物的敏感性；揭示了BRD4可通过调控RAD51等参与DNA损伤修复基因的表达影响细胞损伤修复从而影响药物敏感状态；并发现耐药BRAFV600E黑色素瘤发生氨基酸代谢的显著改变，且BRD4参与其中。本研究的结果揭示了部分BRAFV600E黑色素瘤耐药的表观遗传学特性，从BRD4入手解析了耐药黑色素瘤DNA损伤修复、氨基酸代谢与药物敏感性之间的关系，为解决耐药BRAFV600E突变黑色素瘤的治疗提供新的思路。