Protein kinase C in Lung Cancer with mutant EGFR

EGFR 突变肺癌中的蛋白激酶 C

基本信息

批准号：
10618917
负责人：
YUSUF AWNI HANNUN
金额：
--
依托单位：
NORTHPORT VA MEDICAL CENTER
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：
2020-04-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10618917
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 Natural Compound Oncogenic Oranges PDPK1 gene Pathway interactions Patients 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 pharmacologic prevent protein activation protein expression receptor response targeted treatment tumor tumorigenesis

项目摘要

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.

突变型 EGFR (mEGFR) 是肺腺癌亚型的关键驱动因素，可通过特定药物靶向治疗。抑制剂；然而，反应是短暂的，患者几乎总是会复发，因此需要深入治疗我们对 mEGFR 作用机制的了解导致了以下发现。我们发现，mEGFR 中 EGFR 信号的重新布线在蛋白激酶 C (PKC) 中发挥着关键作用。具有 mEGFR 的肿瘤通常会选择非常高水平的 PKCα，并且这些患者预后明显较差，进一步强调了研究 PKC 的必要性，我们发现这增强了。 PKC 的表达导致其持续激活，进而导致 Akt、mTOR 和其他蛋白的激活该提案将重点开发和测试癌症与癌症相关的假设。 mEGFR 需要独立选择 PKCα 的高表达和持续激活，然后发挥作用 mEGFR 在致癌信号传导和生长中发挥关键作用，我们将追求以下具体目标： 1. 定义 PKCα 响应 mEGFR 的持续激活以及 PKCα 在介导关键作用中的作用我们将确定 mEGFR 的信号传导功能并阐明关键机制。定义其在介导 mEGFR 细胞中 Akt 和 mTOR 激活中的作用，并确定是否以及如何我们还将定义所涉及的机制。目标 2. 定义 PKC 在介导 mEGFR 致癌反应中的作用。假设 mEGFR 肺癌中 PKCα 的过度激活介导细胞中的关键致癌特性综上所述，这些结果开始定义一种新的肿瘤发生协调途径。此外，这些新的结果可能构成了对 PKC 通路上瘾的癌症。我们对 PKC 调节机制及其对癌症生物学和意义的理解的范式转变治疗，特别是防止出现 EGFR 抑制剂耐药性。