A kinase-independent role for EGFR in p38MAPK suppression and S-phase progression in head and neck cancer

EGFR 在头颈癌 p38MAPK 抑制和 S 期进展中的激酶独立作用

基本信息

批准号：
9885259
负责人：
ALAN C RAPRAEGER
金额：
$ 48.06万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-05-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/9885259
关键词：
ABL1 gene Binding Biological Assay Breast Carcinoma Cancer Model Carcinoma Cell Cycle Arrest Cell Cycle Progression Cell Surface Receptors Cells Clinic Clinical Complex Coupled Cytoplasmic Tail DNA biosynthesis Dependence Diagnosis Disease Disease Progression Docking Dysplasia Epidermal Growth Factor Receptor Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Epithelial Epithelial Cells Epithelium Etiology Event Exhibits Extracellular Domain FDA approved Family Goals Growth Growth Factor Receptors Head Cancer Head and Neck Cancer Head and Neck Neoplasms Homologous Gene Human Human Papillomavirus Human papillomavirus 16 Hyperplasia In Vitro Integrin alpha6beta4 Integrins Laboratories Laminin MET gene MST1R gene Malignant Epithelial Cell Malignant Neoplasms Metabolic Modeling Molecular Mus Mutagenesis Neck Cancer Nuclear Oncogenic Oxidative Stress Papilloma Peptides Pharmaceutical Preparations Phosphorylation Phosphotransferases Play Premalignant Cell Protein Tyrosine Kinase Receptor Protein-Tyrosine Kinases Receptor Signaling Refractory Regulation Role S Phase S Phase Arrest Signal Transduction Site Stress Testing Therapeutic Transmembrane Domain Xenograft procedure base cancer cell combat efficacy testing experience extracellular genotoxicity head and neck cancer patient human papilloma virus oncogene in vivo insight member mouse model neoplastic cell new therapeutic target novel oral cavity epithelium outcome forecast overexpression peptide drug peptidomimetics premalignant prevent receptor success syndecan syndecan-4 therapeutic target tumor tumor progression

ABL1 gene Binding Biological Assay Breast Carcinoma Cancer Model Carcinoma Cell Cycle Arrest Cell Cycle Progression Cell Surface Receptors Cells Clinic Clinical Complex Coupled Cytoplasmic Tail DNA biosynthesis Dependence Diagnosis Disease Disease Progression Docking Dysplasia Epidermal Growth Factor Receptor Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Epithelial Epithelial Cells Epithelium Etiology Event Exhibits Extracellular Domain FDA approved Family Goals Growth Growth Factor Receptors Head Cancer Head and Neck Cancer Head and Neck Neoplasms Homologous Gene Human Human Papillomavirus Human papillomavirus 16 Hyperplasia In Vitro Integrin alpha6beta4 Integrins Laboratories Laminin MET gene MST1R gene Malignant Epithelial Cell Malignant Neoplasms Metabolic Modeling Molecular Mus Mutagenesis Neck Cancer Nuclear Oncogenic Oxidative Stress Papilloma Peptides Pharmaceutical Preparations Phosphorylation Phosphotransferases Play Premalignant Cell Protein Tyrosine Kinase Receptor Protein-Tyrosine Kinases Receptor Signaling Refractory Regulation Role S Phase S Phase Arrest Signal Transduction Site Stress Testing Therapeutic Transmembrane Domain Xenograft procedure base cancer cell combat efficacy testing experience extracellular genotoxicity head and neck cancer patient human papilloma virus oncogene in vivo insight member mouse model neoplastic cell new therapeutic target novel oral cavity epithelium outcome forecast overexpression peptide drug peptidomimetics premalignant prevent receptor success syndecan syndecan-4 therapeutic target tumor tumor progression

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项目摘要

Head & Neck cancer (HNC) is the sixth most prevalent cancer worldwide, with over 600,000 new diagnoses annually. Epidermal growth factor receptor (EGFR) is overexpressed in HNC and leads to poor prognosis. Surprisingly, however, FDA-approved drugs that inhibit canonical EGFR signaling have had limited success in the clinic, suggesting that disease progression relies on non-canonical mechanisms of EGFR signaling. We have discovered such a non-canonical mechanism that consists of a hexameric receptor complex organized by syndecan-4 (Sdc4) containing EGFR, the hepatocyte growth factor receptor homologue MST1R/RON, the laminin-binding α3β1 and α6β4 integrins, and a second syndecan, Sdc2. RON and the cytoplasmic/nuclear kinase c-Abl become constitutively activated when incorporated into this complex, suppressing activation of p38MAPK that would otherwise cause immediate cessation of DNA synthesis and S-phase arrest. A peptide (SSTNEGFR) that represents the extracellular docking site in Sdc4 competitively blocks the formation and signaling of this receptor complex. Preliminary findings show that SSTNEGFR prevents the invasion of HNC cells and induces their rapid cell cycle arrest. Whereas invasion relies on active EGFR, cell cycle progression depends on EGFR but not its kinase activity, identifying a non-canonical EGFR signaling mechanism that is likely to be a critical new therapeutic target in cancers such as HNC that overexpress EGFR. Remarkably, SSTNEGFR does not cause cell cycle arrest in normal oral epithelial cells. Specifically, we plan to: (1) define the molecular organization and signaling mechanism of the Sdc:RTK:ITG complex, focusing on molecular interactions used by the two syndecans to assemble this complex, (2) identify the c-Abl and p38MAPK targets that govern stress signaling and S-phase arrest, and (3) test the efficacy of SSTNEGFR against human HNC patient-derived xenografts (PDXs) and the 4-NQO mouse model of HNC to determine at what stages in the initiation and progression HNC the therapeutic is effective. Our goal will be to understand the molecular underpinnings of this unique receptor complex, understand how it drives HNC and identify it as a possible new target for therapeutics to treat HN disease.

Head＆Neck Cancer（HNC）是全球第六大癌症，有超过600,000个新诊断表皮生长因子受体（EGFR）在HNC中过表达，导致预后不良。然而，令人惊讶的是，抑制规范EGFR信号的FDA批准的药物在该诊所表明疾病进展依赖于EGFR信号传导的非规范机制。我们有发现了这样一种非典型机制，该机制由由六聚体接收器组成的复合物组成 Syndecan-4（SDC4）含有EGFR，肝细胞生长因子受体同源物MST1R/RON，层粘连蛋白结合的α3β1和α6β4整合素，以及第二个syndecan，sdc2。罗恩和细胞质/核当掺入该复合物中时，激酶C-ABL被组成式激活，抑制激活的激活 p38mapk否则会立即停止DNA合成和S期停止。胡椒（SSTNEGFR）代表SDC4中细胞外对接位点的（竞争性地都会阻止形成和信号传导）这个接收器复合物。初步发现表明，SSTNEGFR防止了HNC细胞的侵袭和诱导它们快速的细胞周期停滞。而入侵依赖于主动EGFR，而细胞周期的进程取决于在EGFR上，而不是其激酶活性，确定可能是一种非典型的EGFR信号传导机制过表达EGFR的HNC等癌症中关键的新治疗靶标。值得注意的是，Sstnegfr确实如此不会引起正常口腔上皮细胞中的细胞周期停滞。具体而言，我们计划：（1）定义分子 SDC：RTK：ITG复合物的组织和信号传导机制，重点是使用的分子相互作用两个联合体组装这一复合物，（2）确定控制压力的C-ABL和P38MAPK目标信号传导和S期停滞，以及（3）测试SSTNEGFR对人HNC患者衍生的效率异种移植物（PDXS）和HNC的4-NQO小鼠模型，以确定主动性和主动性阶段的哪个阶段进展HNC治疗是有效的。我们的目标是了解这一点的分子基础独特的接收器复合物，了解它如何驱动HNC并将其识别为可能的新目标治疗HN疾病。