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

Gαq/GNAQ 致癌信号电路中的靶向系统漏洞：新精度 葡萄膜黑色素瘤的治疗 G 蛋白偶联受体 (GPCR) 代表参与信号的最大细胞表面蛋白家族 GPCR 发挥着关键的生理作用，其功能障碍导致了一些最常见的疾病。 令人惊讶的是，我们最近对人类疾病的分析表明，它们成为超过 25% 的治疗药物的目标。 人类癌症基因组揭示了 G 蛋白和 GPCR 中意想不到的高频率突变 事实上，近 30% 的人类癌症都存在 GPCR 或 G 蛋白突变。 致瘤潜力正在研究中，激活 GNAQ 和 GNA11（本文称为 GNAQ）的突变 癌基因，编码 GTP 酶缺陷和组成型活性 Gαq 蛋白），在约 93% 的 葡萄膜黑色素瘤 (UM) 和皮肤黑色素瘤 (SKCM) 分别占 4%，它们充当致癌物质 UM 是成人中最常见的原发性眼部癌症，影响超过 2,500 名患者。 仅在美国一年，就有近 50% 的人死于肝转移，迄今为止，尚无有效的治疗方法。 我们最近证明 YAP 激活是 UM 的核心。 生长并发现了 Gαq-FAK 驱动的酪氨酸磷酸化网络与 YAP 之间的新型直接联系 我们的中心假设是，这种信号特异性可能代表系统漏洞。 我们的总体假设是我们提出的。 针对作用于 Gαq 下游的 FAK 及其补偿性（抵抗性）或合成致死性的研究 （敏化）机制将为晚期和 mUM 提供癌基因特异性治疗方法， 最终，我们的前提是增加抗肿瘤活性，同时降低毒性和副作用。 FAK 是 GNAQ 致癌途径的一个组成部分，反过来，FAK 阻断具有临床相关性 FAK 抑制剂 (FAKi) 可能代表一种单独或部分治疗 mUM 的精准治疗方法 或作为基于信号转导的新型精确联合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. 建立治疗方法。 目标 3. FAKi/MEKi 耐受性的表征。 持久种群和获得性耐药机制