Protein kinase C in Lung Cancer with mutant EGFR

EGFR 突变肺癌中的蛋白激酶 C

• 批准号: 10454776
• 负责人: YUSUF AWNI HANNUN
• 金额: --
• 依托单位: NORTHPORT VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10454776
• 关键词: Acute; Cancer Biology; Cell Line; Cell membrane; Cells; Critical Pathways; Data; Development; Diglycerides; Drug resistance; Enzymes; Epidermal Growth Factor Receptor; Evolution; FRAP1 gene; Family; Foundations; G-Protein-Coupled Receptors; Goals; Growth; Growth Factor; Isoenzymes; Laboratories; Light; Lipids; Lung Adenocarcinoma; Malignant Neoplasms; Malignant neoplasm of lung; Mediating; Membrane; Mutation; Oncogenic; Oranges; PDPK1 gene; Pathway interactions; Patients; Pharmacology; Phospholipase C; Phosphorylation; Play; Prevention; Prognosis; Property; Protein Inhibition; Protein Kinase C; Protein translocation; Proteins; Receptor Protein-Tyrosine Kinases; Receptor Signaling; Regulation; Relapse; Resistance; Role; Scheme; Signal Pathway; Signal Transduction; Signaling Protein; Testing; Therapeutic; Tumor Promoters; Work; cell behavior; cell growth; in vivo; inhibitor; lung cancer cell; member; mutant; novel; novel therapeutics; overexpression; prevent; protein activation; protein expression; receptor; response; targeted treatment; tumor; tumorigenesis

Mutant EGFR (mEGFR) is a key driver of a subset of lung adenocarcinoma that is targetable by specific inhibitors; however, responses are transient, and patients almost always relapse, thus necessitating a deep understanding of the mechanisms involved in the action of mEGFR. Our studies are leading to the discovery of rewiring of EGFR signaling in mEGFR with a pivotal role played by protein kinase C (PKC). We find that patients with tumors having mEGFR often show a selection for very high levels of PKC, and these patients have substantially worse prognosis, further underscoring the need to study PKC. We find that this enhanced expression of PKC results in its sustained activation which then results in the activation of Akt, mTOR, and other downstream targets. This proposal will focus on developing and testing the hypothesis that cancers with mEGFR require independent selection for high expression and sustained activation of PKC which then plays a key role in allowing oncogenic signaling and growth by mEGFR. We will pursue the following specific aims: Aim 1. Define the sustained activation of PKC in response to mEGFR and the role of PKC in mediating key signaling functions of mEGFR and elucidate key mechanisms. We will establish the activation of PKC and define its roles in mediating the activation of Akt and mTOR in mEGFR cells and determine if and how the induction of cPKC switches signaling downstream of mEGFR. We will also define the mechanisms involved. Aim 2. Define the role of PKC in mediating oncogenic responses to mEGFR. Here will evaluate the hypothesis that hyper-activation of PKC in mEGFR lung cancers mediates critical oncogenic properties in cells and in vivo. Taken together, these results are beginning to define a novel coordinated pathway of oncogenesis in those cancers that become addicted to the PKC pathway. Moreover, these novel results may constitute a paradigm shift in our understanding of mechanisms regulating PKC and its significance to cancer biology and therapeutics, especially in preventing emergence of resistance to EGFR inhibitors.

突变EGFR（MEGFR）是肺腺癌子集的关键驱动力 抑制剂；但是，反应是短暂的，患者几乎总是中继，因此 了解MEGFR作用所涉及的机制。我们的研究导致发现 蛋白激酶C（PKC）扮演的关键作用在MEGFR中重新布线EGFR信号传导。我们发现患者 由于肿瘤具有MEGFR通常会显示出非常高的PKC的选择，并且这些患者具有 预后较差，进一步强调了研究PKC的需求。我们发现这增强了 PKC的表达导致其持续激活，从而导致Akt，mTOR和其他的激活 下游目标。该提案将着重于开发和检验与癌症有关的假设 MEGFR需要独立的选择才能高表达和持续激活PKC，然后发挥 MEGFR允许致癌信号传导和生长的关键作用。我们将追求以下具体目标：目标 1。定义PKC的持续激活，以响应MEGFR和PKC在介导键中的作用 MEGFR和阐明关键机制的信号传导功能。我们将建立PKC的激活和 定义其在介导MeGFR细胞中Akt和MTOR激活的角色中的作用，并确定是否以及如何以及如何 CPKC开关的诱导MEGFR下游信号传导。我们还将定义涉及的机制。 AIM 2。定义PKC在介导对MEGFR的致癌反应中的作用。这里将评估 假设MEGFR肺癌中PKC的过度激活介导细胞中的关键致癌特性 和体内。综上所述，这些结果开始定义一种新型的肿瘤发生途径 在那些沉迷于PKC途径的癌症中。而且，这些新颖的结果可能构成 我们对调查PKC的机制的理解及其对癌症生物学的意义和 治疗剂，特别是在防止对EGFR抑制剂抗性的出现时。