Defining the role of NF1 and SPRED1 loss in melanoma

项目总结/摘要 在黑色素瘤中，NF 1功能缺失突变是继活化后第三常见的致癌性改变。 BRAF和NRAS突变。RAS GTP酶激活蛋白NF 1提供了来自 MAPK途径通过与质膜上的SPRED 1结合而使RAS-GTP失活。我们 最近在黑色素瘤中发现了SPRED 1的复发性失活突变， 具有失活NF 1突变的排他性模式，与它们的功能重叠一致。灭活 肿瘤抑制因子通常与另外的MAPK激活突变共发生，例如 试剂盒我们假设NF 1或SPRED 1失活可能会降低KIT治疗抑制的疗效。 以及MAPK通路中类似的功能改变增益。本研究的目的是确定 在NF 1或SPRED 1丢失的情况下发生的额外MAPK激活改变的谱， 确定NF 1或SPRED 1在黑色素瘤进展和对靶向治疗的反应中的作用。我们 中心假设是NF 1或SPRED 1缺失增加MAPK信号传导，但完全恶性转化 需要对MAPK通路进行额外的改变。我们将对合作者的范围进行分类 与NF 1或SPRED 1失活形成致癌对，并证实它们对致瘤性的贡献 无论是在体外还是在体内。我们假设，识别致癌基因对和开发治疗策略 解决一对中的两个成员将导致改善患者的结果。我们会提供证据 这一概念的基本原理是基于我们的初步数据，即KIT和MEK的双重抑制是协同的 对于具有由KIT突变和NF 1或SPRED 1缺失组成的致癌对的黑素瘤。我们将测试 在基因工程改造的人黑素瘤细胞系和小鼠模型中的联合疗法。我们还将 调查KIT和SPRED 1之间的直接物理相互作用，这可能会导致更多的途径， 抑制具有KIT或SPRED 1突变的黑素瘤。这项工作将为类似的研究提供一个框架， NF 1和SPRED 1的其他合作者。这项研究意义重大，因为它将导致新的治疗方法， 大量的黑色素瘤患者目前没有靶向治疗。的 拟议的研究是创新的，因为它测试了一个新的假设，为什么治疗突变，如KIT 对黑色素瘤的疗效有限。将光线投射到复杂的信号通路扰动上， 相当大比例的具有NF 1或SPRED 1的黑色素瘤将对具有NF 1或SPRED 1的患者产生相当大的影响。 目前治疗选择有限的黑素瘤。

Project Summary/Abstract In melanoma, loss of function mutations in NF1 are the third most common oncogenic alteration after activating mutations in BRAF and NRAS. The RAS GTPase-activating protein NF1 provides negative feedback from the MAPK pathway to RAS by binding to SPRED1 at the plasma membrane where it is inactivates RAS-GTP. We recently discovered recurrent inactivating mutations of SPRED1 in melanoma, occurring in a mutually exclusive pattern with inactivating NF1 mutations, consistent with their functional overlap. Inactivation of either tumor suppressor often co-occurs with additional MAPK activating mutations such as activating mutations of KIT. We hypothesize that NF1 or SPRED1 inactivation may reduce the efficacy of therapeutic inhibition of KIT and similar gain of function alterations in the MAPK pathway. The objective of this research is to identify the spectrum of additional MAPK activating alterations that occur in the setting of NF1 or SPRED1 loss and to determine the role of NF1 or SPRED1 in melanoma progression and response to targeted therapies. Our central hypothesis is that NF1 or SPRED1 loss increases MAPK signaling but that full malignant transformation requires additional alterations that feed into the MAPK pathway. We will catalogue the spectrum of cooperators that form oncogenic pairs with NF1 or SPRED1 inactivation and validate their contributions to tumorigenicity both in vitro and in vivo. We hypothesize that identifying oncogenic pairs and developing therapeutic strategies that address both members of a pair will lead to improved outcomes for patients. We will provide proof of principle for this concept by building on our preliminary data that dual inhibition of KIT and MEK are synergistic for melanomas with an oncogenic pair consisting of KIT mutation and NF1 or SPRED1 loss. We will test combination therapies in genetically engineered human melanoma cell lines and mouse models. We will also investigate the direct physical interaction between KIT and SPRED1, which may lead to additional avenues for inhibiting melanomas with KIT or SPRED1 mutations. This work will provide a framework for similar studies for other cooperators of NF1 and SPRED1. This research is significant since it will lead to novel therapies for a significant number of melanoma patients for whom targeted therapies are not currently available. The proposed research is innovative because it tests a novel hypothesis why treatment of mutations such as KIT have limited efficacy in melanoma. Shedding light onto the complex signaling pathway perturbations in the considerable share of melanomas with NF1 or SPRED1 will have a considerable impact for patients with melanomas for which treatment options are currently limited.