Targeting Sox10-low cells in drug-resistant melanoma

最近黑色素瘤靶向治疗的大部分焦点都集中在MAPK通路上，该通路在 大约90%的黑色素瘤(其中一半以上表达BRAFV600E)。目前的靶向治疗，如 维莫拉非尼(BRAFV600E抑制剂)或BRAF和MEK抑制剂的联合治疗产生深刻的初始 大多数表达BRAFV600E的肿瘤的反应。然而，这些反应往往是短暂的和抵抗的 通常在几个月内发病。基因组分析未能确定40%人类的耐药性机制 皮肤黑色素瘤。发现新的BRAFi抗性途径将产生新的药物靶点和治疗方法 治疗黑色素瘤的方法。 Sox10下调监管促进了BRAFi阻力。我的初步数据表明，获得性细胞系模型 低Sox10的维莫拉非尼抗性激活了RhoA途径。除了RhoA在调节 在细胞骨架方面，RhoA还可以通过激活多个转录共激活因子(如MRTF- A和YAP1)。我的初步数据显示，在Sox10低BRAFi抗性中，MRTF-A和YAP1也被激活 细胞。这项提案的目标是确定Sox10损失促进BRAFi的下游机制 抵抗。这一点很重要，因为Sox10的损失是Vemurafenib耐药的主要机制，但我们缺乏方法来 有效地瞄准这些细胞。SOX10的缺失也可能促进转移和免疫逃避，所以要找到靶向的方法 SOX10Low细胞可能有益于黑色素瘤治疗的其他方面。 使用综合方法，这项提案中的工作将结合生物信息学、分子生物学和细胞生物学， 药理学和临床前体内异种移植模型I：1)确定SOX10缺失促进的机制 BRAFi耐药性和2)针对RhoA调节的基因转录和MAPK的联合药物治疗 途径采用体内PDX模型。 这项工作的长期目标是开发有效的治疗方法来改进黑色素瘤的治疗。成功 这项提案的完成将为设计针对MAPK的联合疗法提供临床前的理论基础 途径和RhoA调控的基因转录。

Much of the recent focus of melanoma targeted therapy has been on the MAPK pathway, which is aberrantly activated in approximately 90% of melanoma tumors (over half of which express BRAFV600E). Current targeted therapies such as Vemurafenib (BRAFV600E inhibitor), or a combination therapy of BRAF and MEK inhibitors produce a profound initial response in a majority of BRAFV600E expressing tumors. However, these responses are often short-lived and resistance typically develops within months. Genomic analysis has failed to identify resistance mechanisms in >40% of human cutaneous melanoma tumors. Identifying novel BRAFi-resistance pathways will yield new drug targets and therapeutic approaches to treat melanoma. Sox10 downregulation promotes BRAFi resistance. My preliminary data suggests that cell line models of acquired Vemurafenib resistance with low Sox10 activate the RhoA pathway. In addition to the role of RhoA in regulating the cytoskeleton, RhoA can also regulate gene expression by activating multiple transcriptional co-activators (such as MRTF- A and YAP1). My preliminary data demonstrates that MRTF-A and YAP1 are also activated in Sox10Low BRAFi-resistant cells. The objective of this proposal is to identify the downstream mechanisms by which Sox10 loss promotes BRAFi resistance. This is important, since Sox10 loss is a major Vemurafenib resistance mechanism, but we lack approaches to effectively target these cells. Sox10 loss may also promote metastasis, and immune-evasion, so finding ways to target Sox10Low cells could be beneficial for other aspects of melanoma therapy. Using an integrated approach, work in this proposal will combine bioinformatics, molecular and cellular biology, pharmacology, and pre-clinical in vivo xenograft models I will: 1) Identify the mechanisms by which Sox10 loss promotes BRAFi resistance and 2) Test combination drug therapies targeting RhoA-regulated gene transcription and the MAPK pathway using in vivo PDX models. The long-term goal of this work is to develop effective therapies for the improved treatment of melanoma. Successful completion of this proposal will provide pre-clinical rationale for designing combination therapies targeting the MAPK pathway and RhoA-regulated gene transcription.