Molecular mechanisms of focal adhesion kinase in promoting hepatocarcinogenesis

摘要 肝细胞癌（HCC）在全世界造成60多万人死亡，在美国造成12，000人死亡。 国家每年。HCC患者的总生存率低于18%，大多数HCC患者 有限的治疗选择。迫切需要开发新的和更有效的治疗策略 和治疗肝细胞癌的药物。多年来，我们已经确定粘着斑激酶（FAK）作为一个有前途的目标 来治疗HCC。我们发现FAK在16%的HCC标本中扩增和过表达。我们发现 肝细胞中Fak的缺失抑制c-Met（MET）/β-catenin（CAT）诱导的HCC肿瘤生长， 延长动物的生存期。我们证明FAK激酶活性对HCC的发展至关重要， FAK激酶抑制剂有效抑制HCC肿瘤生长。我们进一步发现， 在小鼠肝脏中，FAK和CAT都不足以导致HCC形成，但FAK和CAT单独存在都不足以导致HCC形成 通过增加AR的表达。尽管所有这些令人兴奋的发现，更多的研究是必要的， 更好地了解FAK在肝癌中发挥作用的分子机制。整体 本基金的目的是回答三个问题：1，FAK如何促进HCC生长？2、我们能不能针对 FAK能提高目前靶向治疗的疗效吗？3，随着HCC细胞获得对FAK抑制剂的抗性 治疗时，我们如何克服这种阻力？在该提案中，Aim 1将研究FAK过表达如何 促进糖酵解。目标2将研究靶向FAK是否会改善乐伐替尼的疗效。目标3将 剖析HCC细胞获得对FAK抑制的抗性的机制。本研究的结果 将为以FAK为靶点的肝癌治疗提供重要的机制依据。

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.