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

头颈癌（HNC）是全球第六大流行癌症，有超过60万例新诊断 每年。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，FDA批准的抑制典型EGFR信号传导的药物在治疗中的成功有限。 临床，表明疾病进展依赖于EGFR信号传导的非经典机制。我们有 发现了这样一种非经典机制，它由六聚体受体复合物组成， 多配体蛋白聚糖-4（Sdc 4）含有EGFR，肝细胞生长因子受体同源物MST 1 R/罗恩， 层粘连蛋白结合α3β1和α6β4整联蛋白，以及第二多配体蛋白聚糖Sdc 2。罗恩和细胞质/细胞核 激酶c-Abl在掺入该复合物中时被组成性激活，抑制 p38 MAPK，否则会导致DNA合成的立即停止和S期停滞。的肽 代表Sdc 4细胞外对接位点的SSTNEGFR竞争性阻断了Sdc 4的形成和信号传导。 这个受体复合物的。初步研究结果表明，SSTNEGFR阻止HNC细胞的侵袭， 导致细胞周期快速停滞。而侵袭依赖于活性EGFR，细胞周期进程取决于 对EGFR而不是其激酶活性的影响，确定了一种非经典的EGFR信号传导机制， 在癌症中的关键新的治疗靶点，如过表达EGFR的HNC。值得注意的是， 不会导致正常口腔上皮细胞的细胞周期停滞。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，重点关注 两种多配体蛋白聚糖组装成复合物，（2）鉴定控制应激的c-Abl和p38 MAPK靶点 信号传导和S期阻滞，和（3）测试SSTNEGFR针对人HNC患者来源的HNC细胞的功效。 异种移植物（PDX）和HNC的4-NQO小鼠模型，以确定在HNC的起始和 进展HNC的治疗是有效的。我们的目标将是了解这一现象的分子基础 独特的受体复合物，了解它如何驱动HNC，并将其确定为可能的新治疗靶点 治疗HN病

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.