Targeting Systems Vulnerabilities in the Gαq/GNAQ Oncogenic Signaling Circuitry: New Precision Therapies for Uveal Melanoma

GαQ/GNAQ致癌信号电路中的靶向系统漏洞：新的精确度 葡萄膜黑色素瘤的治疗 G蛋白偶联受体(GPCRs)是细胞表面参与信号转导的最大蛋白家族 变速箱。GPCRs发挥着关键的生理作用，它们的功能障碍导致了一些最常见的 人类疾病，使它们成为所有治疗药物的25%的靶子。引人注目的是，我们最近对 人类癌症基因组显示G蛋白和GPCRs出现意外的高频率突变 大多数肿瘤类型。事实上，近30%的人类癌症存在GPCR或G蛋白突变。而他们的 致癌潜力正在研究中，激活GNAQ和GNA11(这里称为GNAQ)的突变 在~93%的人中发现了编码GTP酶缺陷和结构性活性GαQ蛋白的癌基因 葡萄膜黑色素瘤(UM)和4%的皮肤黑色素瘤(SKCM)，它们在这些地方起致癌作用 司机。UM是成人中最常见的原发性眼癌，每个患者都有2500多名患者 仅在美国，每年就有近50%的人死于肝转移。到目前为止，还没有有效的治疗方法 治疗转移性UM病的选择(UM)。我们最近证明了YAP激活是UM的核心 生长并发现G-αQ-FAK驱动的酪氨酸磷酸化网络与YAP之间的新的直接联系 激活。我们的中心假设是，这种信号特异性可能代表了一种系统漏洞，可以 被用来开发新的精准治疗方法。我们的总体假设是，我们提议的 针对GαQ下游的FAK及其代偿性(抵抗力)或合成致死性的研究 (致敏)机制将为晚期和MUM提供癌基因特异性治疗方法。 从而增强了抗肿瘤活性，且毒副作用较小。最终，我们的前提是 FAK是GNAQ致癌途径不可分割的一部分，反过来，FAK阻断与临床相关的 FAK抑制剂(FAKI)可能代表了一种精确的治疗方法，可单独或部分治疗MU。 或作为新的基于信号转导的精确共同靶向策略的一部分。这将从三个方面进行调查： 目标1：利用GNAQ合成致死和基因相互作用网络暴露系统漏洞 导致UM细胞死亡作为治疗MUM的一种精确治疗方法。目的2.建立治疗方法 体内联合靶向G-αQ-FAK调控通路的可能性。目的3.耐Faki/Meki的特性 获得性抗性的持久种群和机制

Targeting Systems Vulnerabilities in the Gαq/GNAQ Oncogenic Signaling Circuitry: New Precision Therapies for Uveal Melanoma G protein-coupled receptors (GPCRs) represent the largest family of cell surface proteins involved in signal transmission. GPCRs play key physiological roles and their dysfunction contributes to some of the most prevalent human diseases, making them the target of >25% of all therapeutic drugs. Strikingly, our recent analysis of human cancer genomes revealed an unanticipated high frequency of mutations in G proteins and GPCRs in most tumor types. Indeed, nearly 30% of human cancers harbor mutations in GPCRs or G proteins. While their tumorigenic potential is under investigation, activating mutations in GNAQ and GNA11 (herein referred as GNAQ oncogenes, which encode GTPase deficient and constitutively active Gαq proteins), were identified in ~93% of uveal melanoma (UM) and 4% of skin cutaneous melanoma (SKCM), respectively, where they act as oncogenic drivers. UM is the most common primary cancer of the eye in adults, affecting more than 2,500 patients each year in the US alone, nearly 50% of which will die from liver metastasis. To date, there are no effective therapeutic options to treat metastatic UM disease (mUM). We recently demonstrated that YAP activation is central to UM growth and uncovered a novel direct link between Gαq-FAK driven tyrosine phosphorylation networks and YAP activation. Our central hypothesis is that this signaling specificity may represent a systems vulnerability that can be exploited for the development of new precision therapies for mUM. Our overall hypothesis is that our proposed studies targeting FAK, which acts downstream from Gαq, and its compensatory (resistance) or synthetic lethal (sensitizing) mechanisms will provide an oncogene-specific therapeutic approach for advanced and mUM, resulting in increased antitumor activity with lower toxicities and fewer side effects. Ultimately, our premise is that FAK is an integral part of the GNAQ oncogenic pathway and that in turn, FAK blockade with clinically relevant FAK inhibitors (FAKi) may represent a precision therapeutic approach for the treatment of mUM, alone or as part or as part of novel signal transduction-based precision co-targeting strategies. This will be investigated in 3 aims: Aim 1: To exploit GNAQ-synthetic lethal and gene interaction networks to expose systems vulnerabilities resulting in UM cell death as a precision therapeutic approach to treat mUM. Aim 2. To establish the therapeutic potential of co-targeting the Gαq-FAK regulated pathway in vivo. Aim 3. Characterization of FAKi/MEKi tolerant persister populations and mechanisms of acquired resistance