Protein kinase C in Lung Cancer with mutant EGFR

EGFR 突变肺癌中的蛋白激酶 C

• 批准号: 9888660
• 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/9888660
• 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; 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; cancer cell; cell behavior; cell growth; in vivo; inhibitor/antagonist; member; mutant; novel; novel therapeutics; outcome forecast; 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.

突变的EGFR(MEGFR)是肺腺癌亚群的关键驱动因素，可通过特异性靶向作用 抑制剂；然而，反应是短暂的，患者几乎总是复发，因此有必要进行深部治疗。 了解mEGFR的作用机制。我们的研究正在导致发现 在蛋白激酶C(PKC)起关键作用的情况下，mEGFR中的EGFR信号重新连接。我们发现，患者 患有mEGFR的肿瘤通常表现出对非常高水平的PKC的选择，这些患者 更糟糕的预后，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 下游目标。这项提案将侧重于开发和测试癌症与癌症 MEGFR需要独立选择才能高表达和持续激活PKC，然后发挥一种 MEGFR在致癌信号和生长中的关键作用。我们将追求以下具体目标：目标 1.明确pkc在mEGFR反应中的持续激活以及pkc在调节Key中的作用 并阐明了mEGFR的信号转导功能和关键机制。我们将建立PKC的激活和 明确其在介导mEGFR细胞Akt和mTOR激活中的作用，并确定是否以及如何 CPKC的诱导与mEGFR下游的信号交换有关。我们还将定义所涉及的机制。 目的2.明确PKC在介导mEGFR致癌反应中的作用。在这里我们将评估 PKc在mEGFR肺癌中过度激活在细胞中介导关键致癌特性的假说 在活体内。综上所述，这些结果开始定义一种新的肿瘤发生的协调途径 在那些对PKC途径上瘾的癌症中。此外，这些新颖的结果可能构成一种 我们对PKC调控机制的理解的范式转变及其对癌症生物学和 治疗学，特别是在防止出现对EGFR抑制剂的耐药性方面。