Targeting Sox10-low cells in drug-resistant melanoma

靶向治疗耐药黑色素瘤中的 Sox10-low 细胞

• 批准号: 9763322
• 负责人: Sean Alexander Misek
• 金额: $ 3.99万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-16 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9763322
• 关键词: Affect; BRAF gene; Bioinformatics; CD8-Positive T-Lymphocytes; CD8B1 gene; Cell Line; Cells; Clinical Data; Combination Drug Therapy; Combined Modality Therapy; Cutaneous Melanoma; Cytoskeleton; Dasatinib; Data; Development; Down-Regulation; Drug resistance; Epigenetic Process; Equilibrium; Frequencies; Gene Expression; Genetic Transcription; Genomics; Goals; Growth; Human; Immune Evasion; Immune checkpoint inhibitor; MAP Kinase Gene; MEKs; Melanoma Cell; Mission; Modeling; Molecular and Cellular Biology; Neoplasm Metastasis; Nuclear; Pathway interactions; Patient-Focused Outcomes; Patients; Pharmacology; Population; Public Health; Relapse; Research; Resistance; Reverse Transcription; Role; Signal Pathway; T-Lymphocyte; Testing; Therapeutic; Transcription Coactivator; Treatment Efficacy; United States National Institutes of Health; Work; Xenograft Model; design; effective therapy; human disease; improved; in vivo; inhibitor/antagonist; knock-down; melanoma; mouse model; new therapeutic target; novel; overexpression; pre-clinical; prevent; resistance mechanism; response; role model; targeted treatment; tumor; tumor microenvironment

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.

最近黑色素瘤靶向治疗的焦点主要集中在MAPK通路上，该通路在黑色素瘤中异常激活。 大约90%的黑素瘤肿瘤（其中超过一半表达BRAFV 600 E）。目前的靶向治疗，如 Vemurafenib（BRAFV 600 E抑制剂）或BRAF和MEK抑制剂的联合治疗产生了深刻的初始疗效。 在大多数表达BRAFV 600 E的肿瘤中，然而，这些反应往往是短暂的， 一般会在几个月内发病基因组分析未能在>40%的人类中确定耐药机制。 皮肤黑素瘤鉴定新的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。 Sox 10下调促进BRAFi抗性。我的初步数据表明，获得性的细胞系模型 具有低Sox 10的Vemurafenib抗性激活RhoA途径。除了RhoA在调节细胞凋亡中的作用外， 细胞骨架，RhoA也可以通过激活多种转录共激活因子（如MRTF- A和YAP 1）。我的初步数据表明，MRTF-A和YAP 1也在Sox 10低BRAFI耐药细胞中被激活。 细胞本提案的目的是确定Sox 10缺失促进BRAFi的下游机制 阻力这一点很重要，因为Sox 10丢失是维罗非尼的主要耐药机制，但我们缺乏解决这一问题的方法。 有效地针对这些细胞。Sox 10缺失也可能促进转移和免疫逃避，因此寻找靶向 Sox 10 Low细胞可能对黑色素瘤治疗的其他方面有益。 使用综合方法，本提案中的工作将联合收割机结合生物信息学、分子和细胞生物学， 我将：1）确定Sox 10缺失促进Sox 10表达的机制， BRAFi抗性和2）测试靶向RhoA调节的基因转录和MAPK的组合药物疗法 使用体内PDX模型。 这项工作的长期目标是开发有效的治疗方法，以改善黑色素瘤的治疗。成功 该提案的完成将为设计靶向MAPK的联合治疗提供临床前依据 途径和RhoA调节的基因转录。

项目成果

Inhibition of the Myocardin-Related Transcription Factor Pathway Increases Efficacy of Trametinib in NRAS-Mutant Melanoma Cell Lines.

• DOI: 10.3390/cancers13092012
• 发表时间: 2021-04-22
• 期刊: Cancers
• 影响因子: 5.2
• 作者: Appleton KM;Palsuledesai CC;Misek SA;Blake M;Zagorski J;Gallo KA;Dexheimer TS;Neubig RR
• 通讯作者: Neubig RR