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

头颈癌(HNC)是世界上第六大最常见的癌症，有60多万新诊断病例 每年一次。表皮生长因子受体(EGFR)在HNC中高表达，预后不良。 然而，令人惊讶的是，FDA批准的抑制规范的EGFR信号转导的药物在 临床研究表明，疾病的进展依赖于EGFR信号的非规范机制。我们有 发现了这样一种非正则机制，它由一个六聚体受体复合体组成，由 含有EGFR的Syndecan-4(SDC4)，肝细胞生长因子受体同系物MST1R/RON， 层粘连蛋白结合α3β1和α6β4整合素，以及第二个Syndecan，Sdc2。RON与细胞质/核 当加入到这个复合体中时，激酶c-Abl就会被结构性地激活，从而抑制 P38MAPK，否则会导致DNA合成立即停止和S时相停止。A肽 (SSTNEGFR)代表SDC4中的胞外对接部位，竞争性地阻止形成和信号转导 这种受体复合体。初步研究结果表明，SSTNEGFR可阻止HNC细胞的侵袭和 诱导它们快速的细胞周期停滞。尽管侵袭依赖于活性的EGFR，但细胞周期进程取决于 而不是它的激酶活性，识别出一种非规范的EGFR信号机制，很可能是 高表达EGFR的HNC等癌症的关键新治疗靶点。值得注意的是，SSTNEGFR做到了 不会引起正常口腔上皮细胞周期停滞。具体地说，我们计划：(1)定义分子 SDC：RTK：ITG复合体的组织和信号机制，重点是 组装这个复合体的两个同步蛋白，(2)识别控制应激的c-Abl和p38MAPK靶标 信号转导和S时相阻滞；(3)检测SSTNEGFR对人HNC患者来源的疗效 异种移植(PDX)和4-NQO小鼠HNC模型，以确定在什么阶段的起始和 进展HNC治疗是有效的。我们的目标是了解这一现象的分子基础 独特的受体复合体，了解它是如何驱动HNC的，并确定它可能是治疗的新靶点 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.