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

靶向系统漏洞中的GαQ/GNAQ致癌信号传导电路：新的精度 紫美黑色素瘤的疗法 G蛋白偶联受体（GPCR）代表了参与信号的最大的细胞表面蛋白家族 传播。 GPCR扮演关键的生理角色，其功能障碍有助于一些最普遍的 人类疾病，使其成为所有治疗药物中25％> 25％的靶标。令人惊讶的是，我们最近对 人类癌症基因组揭示了G蛋白和GPCR中意外的高频突变频率 大多数肿瘤类型。实际上，几乎30％的人类癌症中有GPCR或G蛋白中的突变。而他们的 肿瘤势正在研究中，激活了GNAQ和GNA11中的突变（此处称为GNAQ 在〜93％ 卵子黑色素瘤（UM）和4％的皮肤皮肤黑色素瘤（SKCM），它们充当致癌 司机。 UM是成年人中最常见的眼睛原发性癌症，每人影响2500多名患者 仅在美国，几乎50％将死于肝转移。迄今为止，还没有有效的疗法 治疗转移性UM疾病（MUM）的选择。我们最近证明YAP激活是UM的核心 生长并发现GαQ-FAK之间的新型直接联系驱动酪氨酸磷酸化网络和YAP 激活。我们的核心假设是，该信号传导特异性可能代表一个系统漏洞 为开发妈妈的新精密疗法而探索。我们的总体假设是我们提出的 针对FAK的研究，该研究起源于GαQ下游，其代偿性（抗性）或合成致死 （敏化）机制将为高级和妈妈提供一种特异性的治疗方法， 导致抗肿瘤活性增加，毒性较低，副作用较少。最终，我们的前提是 该FAK是GNAQ致癌途径不可或缺的一部分，而该途径又是临床上相关的FAK glocade FAK抑制剂（FAKI）可能是单独或单独或作为一部分的妈妈治疗的精确疗法 或作为新型信号翻译的精确共同目标策略的一部分。这将在3个目标中进行调查： 目的1：利用GNAQ合成致死和基因相互作用网络以暴露系统脆弱性 导致UM细胞死亡是治疗妈妈的精确治疗方法。目标2。建立疗法 在体内共同定位GαQ-FAK调节途径的潜力。目标3。宽容的表征 获得的抗药性和机制