BRAF mutations occur in approximately 50% of melanoma patients. The mutated BRAF kinase continuously activates the mitogen-activated protein kinase (MAPK) pathway to promote cell growth and proliferation. Vemurafenib as a specific BRAF inhibitor can significantly prolong progression-free survival in melanoma patients. However, most patients developed resistance to Vemurafenib after 6 months. The mechanism of drug resistance is not yet fully understood. In this study, we found that proteins secreted by drug-resistant cells protect sensitive cells from Vemurafenib. By RNA-seq, we compared differentially expressed genes between resistant and sensitive cells. We demonstrated that drug-resistant cells secrete more IL-6 protein than sensitive cells. For the first time, we found that IL-6 expressed by drug-resistant cells consists of the following transcripts: IL6-201, IL6-202 and IL6-205. We confirmed that it is the IL6-202 and IL6-205 transcripts that confer drug resistance to Vemurafenib by reactivating the MAPK pathway while IL6-201 is not responsible for the resistance in A375 melanoma cells. Neutralizing IL-6 significantly increased the sensitivity of drug-resistant cells to Vemurafenib. Overall, these results reveal a new mechanism of drug resistance in melanoma.

中文翻译：

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IL-6 的转录本 202 和 205 通过重新激活 BRAF(V600E) 突变黑色素瘤细胞中的 MAPK 途径赋予对 Vemurafenib 的耐药性

大约 50% 的黑色素瘤患者发生 BRAF 突变。突变的 BRAF 激酶持续激活丝裂原激活蛋白激酶 (MAPK) 途径，促进细胞生长和增殖。维莫非尼作为一种特异性 BRAF 抑制剂，可以显着延长黑色素瘤患者的无进展生存期。然而，大多数患者在 6 个月后出现了对 Vemurafenib 的耐药性。耐药性的机制尚未完全清楚。在这项研究中，我们发现耐药细胞分泌的蛋白质可以保护敏感细胞免受维莫非尼的侵害。通过RNA-seq，我们比较了耐药细胞和敏感细胞之间的差异表达基因。我们证明耐药细胞比敏感细胞分泌更多的 IL-6 蛋白。我们首次发现耐药细胞表达的IL-6由以下转录本组成：IL6-201、IL6-202和IL6-205。我们证实，IL6-202 和 IL6-205 转录本通过重新激活 MAPK 途径赋予 Vemurafenib 耐药性，而 IL6-201 与 A375 黑色素瘤细胞中的耐药性无关。中和 IL-6 显着增加耐药细胞对 Vemurafenib 的敏感性。总的来说，这些结果揭示了黑色素瘤耐药的新机制。