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.

突变型EGFR（mEGFR）是肺腺癌的一个亚组的关键驱动因素，其可被特异性EGFR靶向。 抑制剂;然而，反应是短暂的，患者几乎总是复发，因此需要深入的 了解mEGFR的作用机制。我们的研究发现 蛋白激酶C（PKC）在mEGFR中发挥关键作用的EGFR信号转导的重新布线。我们发现病人 具有mEGFR的肿瘤通常显示出对非常高水平的PKC β的选择，并且这些患者 这进一步强调了研究PKC的必要性。我们发现这增强了 PKC的表达导致其持续活化，其随后导致Akt、mTOR和其他细胞因子的活化。 下游目标这项提案将集中于发展和测试癌症与癌症之间的假设。 mEGFR需要高表达的独立选择和PKC β的持续激活，然后PKC β在EGFR的表达中起作用。 mEGFR在允许致癌信号传导和生长中的关键作用。我们将努力实现以下具体目标： 1.确定mEGFR应答中PKC β的持续激活以及PKC β在介导关键免疫应答中的作用。 mEGFR的信号传导功能，并阐明关键机制。我们将建立PKC β的激活， 定义其在介导mEGFR细胞中Akt和mTOR活化中的作用，并确定其是否以及如何介导mEGFR细胞中Akt和mTOR活化。 诱导cPKC β开关mEGFR下游的信号传导。我们还将确定所涉及的机制。 目标2.明确PKC β在介导mEGFR致癌反应中的作用。这里将评估 mEGFR肺癌中PKC β过度活化介导细胞中关键致癌特性的假说 和体内。综合起来，这些结果开始定义一个新的协调的肿瘤发生途径 在那些对PKC途径上瘾的癌症中。此外，这些新的结果可能构成一个新的研究领域。 我们对PKC调节机制及其对癌症生物学意义的理解的范式转变， 本发明的目的是提供一种治疗剂，特别是在预防对EGFR抑制剂的抗性的出现中的用途。