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

针对 Gαq/GNAQ 致癌信号通路中的系统漏洞：葡萄膜黑色素瘤的新精准疗法

• 批准号: 10593130
• 负责人: Andrew Eric Aplin
• 金额: $ 52.58万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10593130
• 关键词: Address; Adult; Affect; CRISPR screen; Cell Death; Cell Line; Cell Surface Proteins; Cell Survival; Cells; Cessation of life; Clinical; Clinical Trials; Combined Modality Therapy; Cutaneous Melanoma; Cytostatics; Development; Diagnosis; Disease; Disease remission; Drug Combinations; Drug resistance; Event; Exposure to; Family; Foundations; Frequencies; Functional disorder; Future; G alpha q Protein; G-Protein-Coupled Receptors; GNAQ gene; GTP-Binding Proteins; Genomics; Growth; Guanosine Triphosphate Phosphohydrolases; Human; Investigation; Link; Liver; Malignant Neoplasms; Melanoma Cell; Metastatic Neoplasm to the Liver; Modeling; Molecular; Molecular Target; Mus; Mutation; Nature; Neoplasm Metastasis; Oncogenes; Oncogenic; PTK2 gene; Pathway interactions; Patients; Pharmaceutical Preparations; Physiological; Play; Population; Positioning Attribute; Precision therapeutics; Primary Lesion; Refractory; Relapse; Resistance; Risk; Role; Sampling; Signal Transduction; Skin; Specificity; System; Therapeutic; Toxic effect; Tyrosine Phosphorylation; United States; Unresectable; Uveal Melanoma; Xenograft Model; cancer genome; cancer type; cell growth; chemotherapy; clinical predictors; clinically relevant; computational pipelines; effective therapy; gene interaction; genetic analysis; human disease; immune checkpoint blockers; in vivo; inhibitor; malignant neoplasm of eye; melanoma; molecular phenotype; multidisciplinary; multimodality; mutant; novel; novel therapeutic intervention; novel therapeutics; predictive marker; prevent; side effect; synergism; therapeutically effective; transmission process; treatment response; tumor; tumorigenic

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

靶向Gαq/GNAQ致癌信号通路中的系统漏洞：新精度 葡萄膜黑色素瘤的治疗 G蛋白偶联受体（GPCR）代表参与信号转导的最大的细胞表面蛋白家族。 传输GPCR起着关键的生理作用，它们的功能障碍导致了一些最普遍的疾病， 人类疾病，使其成为所有治疗药物的目标>25%。引人注目的是，我们最近对 人类癌症基因组揭示了G蛋白和GPCR突变的意外高频率， 大多数肿瘤类型事实上，近30%的人类癌症在GPCR或G蛋白中含有突变。而他们的 致瘤潜力正在研究中，激活GNAQ和GNA 11（本文称为GNAQ）中的突变 癌基因，编码GT3缺陷和组成型活性Gαq蛋白），在约93%的 葡萄膜黑色素瘤（UM）和4%的皮肤皮肤黑色素瘤（SKCM），它们分别作为致癌物 司机UM是成人中最常见的原发性眼癌，每个患者都有超过2，500例 仅在美国一年，其中近50%将死于肝转移。迄今为止，还没有有效的治疗方法 治疗转移性UM疾病（mUM）的选择。我们最近证明雅普激活是UM的核心 发现了Gαq-FAK驱动的酪氨酸磷酸化网络和雅普之间的一种新的直接联系 activation.我们的中心假设是，这种信号特异性可能代表了系统的脆弱性， 用于开发新的精确治疗mUM。我们的总体假设是， 针对Gαq下游作用的FAK及其补偿性（抗性）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， 从而增强抗肿瘤活性，降低毒性，减少副作用。最终，我们的前提是 FAK是GNAQ致癌通路的组成部分，而FAK阻断与临床相关的 FAK抑制剂（FAKi）可能代表一种单独或部分治疗mUM的精确治疗方法。 或作为基于新信号转导的精确共靶向策略的一部分。这将在3个目标中进行研究： 目标1：利用GNAQ-合成致死和基因相互作用网络来暴露系统漏洞 导致UM细胞死亡作为治疗mUM的精确治疗方法。目标2.为了建立一种治疗方法 在体内共靶向Gαq-FAK调节途径的潜力。目标3。FAKi/MEKi耐受性的表征 持久种群和获得性抗性机制