Molecular mechanisms of focal adhesion kinase in promoting hepatocarcinogenesis

粘着斑激酶促进肝癌发生的分子机制

• 批准号: 10534149
• 负责人: Wei Qiu
• 金额: $ 36.76万
• 依托单位: LOYOLA UNIVERSITY CHICAGO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-02 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10534149
• 关键词: Animals; Cessation of life; Data; Development; Focal Adhesion Kinase 1; Genetic; Glucose; Glycolysis; Grant; Growth; Hepatocarcinogenesis; Hepatocyte; Hexokinase A; Human; Intervention; Liver; Malignant Epithelial Cell; Malignant Neoplasms; Malignant neoplasm of liver; Molecular; Mus; Patients; Phosphorylation; Phosphotransferases; Play; Primary carcinoma of the liver cells; Resistance; Role; SPINK1 gene; Specimen; Testing; Therapeutic Intervention; United States; beta catenin; improved; kinase inhibitor; novel; overexpression; pharmacologic; response; targeted treatment; therapeutically effective; tumor growth

Abstract Hepatocellular carcinoma (HCC) causes more than 600,000 deaths worldwide and 12,000 deaths in United States per year. The overall survival of patients with HCC is less than 18% and most patients with HCC have limited treatment options. There is an urgent need to develop new and more effective therapeutic strategies and agents to treat HCC. Over the years we have identified focal adhesion kinase (FAK) as a promising target to treat HCC. We found that FAK is amplified and overexpressed in 16% of HCC specimens. We found that deletion of Fak in hepatocytes suppressed c-Met (MET)/β-catenin (CAT)-induced HCC tumor growth and prolonged survival of animals. We demonstrated that FAK kinase activity is critical for HCC development and FAK kinase inhibitors effectively suppressed HCC tumor growth. We further discovered that overexpression of both FAK and CAT, but neither FAK nor CAT alone, in mouse livers was sufficient to lead to HCC formation through an increased expression of AR. Despite all these exciting findings, more studies are warranted in better understanding the molecular mechanisms by which FAK functions in liver cancers. The Overall Objective of this grant is to answer three questions: 1, how does FAK promote HCC growth? 2, can we target FAK to improve the efficacy of current target therapies? 3, as HCC cells acquire resistance to FAK inhibitors treatment, how can we overcome this resistance? In the proposal, Aim1 will examine how FAK overexpression promotes glycolysis. Aim 2 will investigate if targeting FAK will improve the efficacy of lenvatinib. Aim 3 will dissect the mechanisms by which HCC cells acquire resistance to FAK inhibition. The results from this study will provide an important mechanistic basis for therapeutic intervention to treat HCC by targeting FAK.

抽象的 肝细胞癌（HCC）在全球造成超过60万人死亡，曼联12,000人死亡 每年的状态。 HCC患者的整体生存率小于18％，大多数HCC患者患有 有限的治疗选择。迫切需要制定新的，更有效的治疗策略 和代理人治疗HCC。多年来 治疗HCC。我们发现FAK在16％的HCC标本中被扩增和过表达。我们发现 肝细胞中FAK的缺失抑制了C-MET（MET）/β-catenin（CAT）诱导的HCC肿瘤生长和 延长动物的生存。我们证明了FAK激酶活性对于HCC开发至关重要 FAK激酶抑制剂有效地抑制了HCC肿瘤的生长。我们进一步发现了 FAK和CAT都不是单独的FAK和CAT，在小鼠肝脏中都足以导致HCC形成 通过增加的AR表达。尽管有所有这些令人兴奋的发现，但仍有更多的研究 更好地了解FAK在肝癌中起作用的分子机制。总体 这笔赠款的目标是回答三个问题：1，FAK如何促进HCC的增长？ 2，我们可以定位吗 FAK提高目前目标疗法的效率？ 3，随着HCC细胞获得对FAK抑制剂的抗性 治疗，我们如何克服这种抵抗力？在提案中，AIM1将检查FAK如何过表达 促进糖酵解。 AIM 2将调查靶向FAK是否会提高Lenvatinib的效率。目标3意志 剖析HCC细胞获得对FAK抑制的抗性的机制。这项研究的结果 将为靶向FAK提供治疗干预措施治疗HCC的重要机械基础。