文章：

FAK在癌症中的作用：机制发现和临床应用

FAK in cancer: mechanistic findings and clinical applications

原文发布日期：2014-08-07

DOI: 10.1038/nrc3792

类型: Review Article

开放获取: 否

要点：

1. Focal adhesion kinase (FAK) is a non-receptor protein tyrosine kinase that drives tumour growth and metastasis through kinase-dependent and kinase-independent pathways.
2. FAK promotes metastasis by regulating processes involved in tumour cell motility and invasion, including control of focal adhesion and cytoskeletal dynamics, as well as the regulation of matrix metalloproteinase (MMP) surface expression.
3. Tumour growth is enhanced through pro-proliferative and anti-apoptotic functions of FAK.
4. FAK is connected to cancer stem cell and progenitor cell maintenance through kinase-dependent and kinase-independent functions. FAK signals contribute to the malignant outgrowth of these cells.
5. FAK favours tumour progression via the regulation of signalling pathways within cells of the tumour microenvironment, such as endothelial cells, haematopoietic cells, platelets, macrophages and fibroblasts.
6. FAK activity promotes endothelial cell migration, proliferation and survival, and it stimulates tumour angiogenesis. FAK-mediated regulation of endothelial cell permeability can influence tumour metastasis.
7. FAK expression and activity in tumour and endothelial cells is frequently upregulated and correlated with a poor patient prognosis.
8. Several molecules that target FAK kinase activity or its kinase-independent scaffolding function are under investigation in preclinical trials. Promising drug candidates in Phase I or II clinical trials are small molecule ATP-competitive inhibitors.

要点翻译：

1. 黏着斑激酶（FAK）是一种非受体蛋白酪氨酸激酶，通过激酶依赖性和激酶非依赖性途径驱动肿瘤生长与转移。
2. FAK通过调控肿瘤细胞运动与侵袭相关过程促进转移，包括控制黏着斑和细胞骨架动力学，以及调节基质金属蛋白酶（MMP）的表面表达。
3. FAK通过促增殖和抗凋亡功能增强肿瘤生长。
4. FAK通过激酶依赖性和激酶非依赖性功能与癌症干细胞及祖细胞的维持相关。FAK信号传导促进这些细胞的恶性增殖。
5. FAK通过调控肿瘤微环境细胞（如内皮细胞、造血细胞、血小板、巨噬细胞和成纤维细胞）内的信号通路促进肿瘤进展。
6. FAK活性可促进内皮细胞迁移、增殖和存活，并刺激肿瘤血管生成。FAK介导的内皮细胞通透性调控可影响肿瘤转移。
7. FAK在肿瘤细胞和内皮细胞中的表达及活性常上调，并与患者不良预后相关。
8. 目前已有多个靶向FAK激酶活性及其非激酶支架功能的分子进入临床前试验阶段。处于I期或II期临床试验的有望候选药物主要为小分子ATP竞争性抑制剂。

英文摘要：

Focal adhesion kinase (FAK) is a cytoplasmic protein tyrosine kinase that is overexpressed and activated in several advanced-stage solid cancers. FAK promotes tumour progression and metastasis through effects on cancer cells, as well as stromal cells of the tumour microenvironment. The kinase-dependent and kinase-independent functions of FAK control cell movement, invasion, survival, gene expression and cancer stem cell self-renewal. Small molecule FAK inhibitors decrease tumour growth and metastasis in several preclinical models and have initial clinical activity in patients with limited adverse events. In this Review, we discuss FAK signalling effects on both tumour and stromal cell biology that provide rationale and support for future therapeutic opportunities.

摘要翻译： 

黏着斑激酶（FAK）是一种胞浆蛋白酪氨酸激酶，在多种晚期实体瘤中高表达并被激活。FAK通过对肿瘤细胞及肿瘤微环境中基质细胞的作用，促进肿瘤进展与转移。其激酶依赖性和非激酶依赖性功能共同调控细胞运动、侵袭、存活、基因表达及肿瘤干细胞的自我更新。小分子FAK抑制剂在多种临床前模型中可降低肿瘤生长和转移，并在患者中显示出初步临床活性且不良反应有限。本文综述了FAK信号对肿瘤及基质细胞生物学的影响，为未来的治疗机遇提供理论依据与支持。

原文链接：

FAK in cancer: mechanistic findings and clinical applications