Novel targets of treatment for NF1-mutant melanoma

项目摘要 1型神经纤维瘤病（NF 1）肿瘤抑制基因的体细胞突变在15-25%的 黑色素瘤，并涉及活化的丝裂原活化蛋白激酶（MAPK）信号传导和肿瘤生长。 NF 1突变的临床和生物学相关性知之甚少。有证据表明NF 1突变体 （NF 1-MT）黑色素瘤与较高的肿瘤突变负荷（TMB）相关。然而，NF 1突变并不 与黑色素瘤对免疫疗法的更好反应相关。研究还表明，NF 1-MT 黑色素瘤对MEK或ERK抑制剂敏感，但最近的一份报告显示，NF 1突变并不能预测 对这些药物的敏感性迄今为止，在NF 1-MT黑色素瘤中还没有鉴定和验证可操作的靶点， 并且还没有开发出利用其生物学特性的亚型特异性疗法。我们整合的基因组， 转录组学和蛋白质组学分析表明，增加细胞周期进程是NF 1-κ B的标志。 突变型黑色素瘤，这可能是一种新的治疗策略。因此，我们假设NF 1- 突变型黑色素瘤在生物学上不同于NF 1野生型肿瘤， 表型，不能仅通过MAPK激活来解释，其特征在于细胞周期增加 进展，这使得它们容易受到细胞周期进展和细胞的药理学抑制 增殖，如靶向CDK 4/6或CDC 20的试剂，单独或与MEK抑制组合，或 抑制Shp 2，一种独立于突变BRAF促进MAPK途径活化的磷酸酶 或NRAS。在这个项目中，我们将使用黑色素瘤患者的组织，细胞系和患者来源的肿瘤模型， 小鼠，以阐明黑色素瘤中NF 1突变的生物学和临床影响，并测试新的策略 通过靶向细胞周期进程来治疗这种独特的黑色素瘤分子亚型。我们的发现将提供 为进一步开发治疗NF 1突变型肿瘤的创新性、亚型特异性策略奠定了基础。

PROJECT SUMMARY Somatic mutations in the Neurofibromatosis type 1 (NF1) tumor suppressor gene are reported in 15-25% of melanomas and are implicated in activated mitogen-activated protein kinase (MAPK) signaling and tumor growth. The clinical and biological relevance of NF1 mutations is poorly understood. Evidence suggests that NF1-mutant (NF1-MT) melanoma is associated with a higher tumor mutation burden (TMB). However, NF1 mutations are not associated with better response of melanoma to immunotherapy. Studies have also suggested that NF1-MT melanomas are sensitive to MEK or ERK inhibitors, but a recent report showed that NF1 mutations do not predict sensitivity to these drugs. To date no actionable targets have been identified and validated in NF1-MT melanoma, and no subtype-specific therapy that exploits its biology has been developed. Our integrated genomic, transcriptomic, and proteomic analyses suggest that increased cell cycle progression is a hallmark of NF1- mutant melanomas, which might be exploited as a novel treatment strategy. Hence, we hypothesize that NF1- mutant melanomas are biologically distinct from NF1-wild type tumors, and possess a hyper-proliferative phenotype, that cannot be explained only by MAPK activation and characterized by increased cell cycle progression, which renders them vulnerable to pharmacological inhibition of cell cycle progression and cell proliferation, such as agents targeting CDK4/6 or CDC20, alone or in combination with MEK inhibition, or inhibition of Shp2, a phosphatase that contributes to MAPK pathway activation independently of mutant BRAF or NRAS. In this project, we will use melanoma patient tissues, cell lines, and patient-derived tumor models in mice to elucidate the biological and clinical impact of NF1 mutations in melanoma, and to test novel strategies to treat this distinct melanoma molecular subtype by targeting cell cycle progression. Our findings will provide the basis for further development of innovative, subtype-specific strategies for treatment of NF1-mutant tumors.