The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia.
The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia; St. Vincent's Clinical School, Faculty of Medicine, University of New South Wales, St. Vincent's Hospital, Darlinghurst, NSW 2010, Australia.
Pharmacol Ther. 2015 Feb;146:132-49. doi: 10.1016/j.pharmthera.2014.10.001. Epub 2014 Oct 12.
Focal adhesion kinase (FAK) is a key regulator of growth factor receptor- and integrin-mediated signals, governing fundamental processes in normal and cancer cells through its kinase activity and scaffolding function. Increased FAK expression and activity occurs in primary and metastatic cancers of many tissue origins, and is often associated with poor clinical outcome, highlighting FAK as a potential determinant of tumor development and metastasis. Indeed, data from cell culture and animal models of cancer provide strong lines of evidence that FAK promotes malignancy by regulating tumorigenic and metastatic potential through highly-coordinated signaling networks that orchestrate a diverse range of cellular processes, such as cell survival, proliferation, migration, invasion, epithelial-mesenchymal transition, angiogenesis and regulation of cancer stem cell activities. Such an integral role in governing malignant characteristics indicates that FAK represents a potential target for cancer therapeutics. While pharmacologic targeting of FAK scaffold function is still at an early stage of development, a number of small molecule-based FAK tyrosine kinase inhibitors are currently undergoing pre-clinical and clinical testing. In particular, PF-00562271, VS-4718 and VS-6063 show promising clinical activities in patients with selected solid cancers. Clinical testing of rationally designed FAK-targeting agents with implementation of predictive response biomarkers, such as merlin deficiency for VS-4718 in mesothelioma, may help improve clinical outcome for cancer patients. In this article, we have reviewed the current knowledge regarding FAK signaling in human cancer, and recent developments in the generation and clinical application of FAK-targeting pharmacologic agents.
黏着斑激酶（FAK）是生长因子受体和整合素介导信号的关键调节因子，通过其激酶活性和支架功能，调控正常和癌细胞中的基本过程。黏着斑激酶在许多组织来源的原发性和转移性癌症中表达和活性增加，并且通常与不良的临床结局相关，这突出了黏着斑激酶作为肿瘤发展和转移的潜在决定因素的作用。事实上，来自癌症的细胞培养和动物模型的数据提供了强有力的证据，表明黏着斑激酶通过调节肿瘤发生和转移潜能来促进恶性肿瘤，通过高度协调的信号网络来协调细胞存活、增殖、迁移、侵袭、上皮-间充质转化、血管生成和调节癌症干细胞活性等多种细胞过程。在调控恶性特征方面的这种整体作用表明，黏着斑激酶代表了癌症治疗的潜在靶点。虽然针对黏着斑激酶支架功能的药物靶向治疗仍处于早期开发阶段，但目前有许多基于小分子的黏着斑激酶酪氨酸激酶抑制剂正在进行临床前和临床试验。特别是 PF-00562271、VS-4718 和 VS-6063 在选定的实体癌患者中显示出有希望的临床活性。通过实施预测反应生物标志物，如间皮瘤中针对 VS-4718 的 Merlin 缺失，对合理设计的黏着斑激酶靶向药物进行临床测试，可能有助于改善癌症患者的临床结局。在本文中，我们综述了黏着斑激酶信号在人类癌症中的最新知识，以及黏着斑激酶靶向药物的最新发展和临床应用。
