Molecular mechanisms of focal adhesion kinase in promoting hepatocarcinogenesis

摘要 肝细胞癌在全球造成60多万人死亡，在美国造成12,000人死亡 每年的国家数量。肝癌患者的总存活率不到18%，大多数肝癌患者 治疗选择有限。迫切需要开发新的、更有效的治疗策略。 以及治疗肝细胞癌的药物。多年来，我们已经发现粘着斑激酶(FAK)是一个很有希望的靶点 来治疗肝细胞癌。我们发现FAK在16%的肝细胞癌标本中扩增和过度表达。我们发现 肝细胞Fak缺失抑制c-Met(Met)/β-catenin(CAT)诱导的肝癌生长和 延长动物的存活时间。我们证明了FAK激酶活性对肝细胞癌的发生和发展至关重要。 FAK激酶抑制剂有效地抑制了肝癌肿瘤的生长。我们进一步发现，过度表达 在小鼠肝脏中，FAK和CAT都不足以导致肝细胞癌的形成 通过增加AR的表达。尽管有这些令人兴奋的发现，但仍有必要进行更多的研究 更好地了解FAK在肝癌中发挥作用的分子机制。整体而言 这笔赠款的目的是回答三个问题：1，FAK如何促进肝癌生长？2，我们能有针对性地 FAK改善当前靶向治疗的疗效？3，肝癌细胞对FAK抑制剂产生抗药性 治疗，我们怎样才能克服这种阻力呢？在提案中，Aim1将研究FAK如何过度表达 促进糖酵解。目的2将研究靶向FAK是否会改善Lenvatinib的疗效。目标3将 剖析肝癌细胞获得对FAK抑制的抗性的机制。这项研究的结果 将为靶向FAK的肝细胞癌治疗干预提供重要的机制基础。

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.