Wan Ziyu, Zhu Zefeng, Wang Pengbin, Xu Xuan, Ma Tianhao, Li Huari, Li Lexing, Qian Feng, Gu Wei
Anhui Provincial Key Laboratory of Tumor Evolution and Intelligent Diagnosis and Treatment, Department of Biochemistry and Molecular Biology, Bengbu Medical University, Bengbu 233030, China.
College of Life Science and Technology, Wuhan University of Bioengineering, Wuhan 430415, China.
Biomolecules. 2025 Aug 26;15(9):1233. doi: 10.3390/biom15091233.
Focal adhesion kinase (FAK) is a crucial protein component of focal adhesions (FAs) and belongs to the cytoplasmic non-receptor protein tyrosine kinase family. FAK primarily regulates adhesion signaling and cell migration and is highly expressed in various tumors, including lung, liver, gastric, and colorectal cancers, as well as in conditions such as acute lung injury (ALI) and pulmonary fibrosis (PF). Recent research on FAK and its small-molecule inhibitors has revealed that targeting FAK provides a novel approach for treating various lung diseases. FAK inhibitors can obstruct signaling pathways, demonstrating anti-tumor, anti-inflammatory, and anti-fibrotic effects. In lung cancer, FAK inhibitors suppress tumor growth and metastasis; in ALI, they exert protective effects by alleviating inflammatory responses and oxidative stress; and in pulmonary fibrosis, FAK inhibitors reduce fibroblast activation and inhibit collagen deposition. The findings demonstrate promising efficacy and an acceptable safety profile in preclinical models. However, these early-stage results require further validation through clinical studies. Additionally, the underlying mechanisms, as well as the toxic effects and side effects, necessitate further in-depth investigation. Some have progressed to clinical trials (Defactinib (Phase II), PF-562271 (Phase I), CEP-37440 (Phase I), PND-1186 (Phase I), GSK-2256098 (Phase II), BI-853520 (Phase I)), offering potential therapeutic targets for lung diseases. Collectively, these findings establish a foundational basis for the advancement of FAK inhibitor discovery. Emerging methodologies, such as PROTAC degraders and combination regimens, demonstrate significant potential for future research. Based on a comprehensive analysis of the relevant literature from 2015 to the present, this review briefly introduces the structure and function of FAK and discusses recent research advancements regarding FAK and its inhibitors in the context of pulmonary diseases.
粘着斑激酶（FAK）是粘着斑（FAs）的关键蛋白质成分，属于细胞质非受体蛋白酪氨酸激酶家族。FAK主要调节粘着信号传导和细胞迁移，在包括肺癌、肝癌、胃癌和结直肠癌等多种肿瘤中高表达，在急性肺损伤（ALI）和肺纤维化（PF）等病症中也高表达。最近对FAK及其小分子抑制剂的研究表明，靶向FAK为治疗各种肺部疾病提供了一种新方法。FAK抑制剂可阻断信号通路，显示出抗肿瘤、抗炎和抗纤维化作用。在肺癌中，FAK抑制剂可抑制肿瘤生长和转移；在ALI中，它们通过减轻炎症反应和氧化应激发挥保护作用；在肺纤维化中，FAK抑制剂可减少成纤维细胞活化并抑制胶原蛋白沉积。这些发现在临床前模型中显示出有前景的疗效和可接受的安全性。然而，这些早期结果需要通过临床研究进一步验证。此外，其潜在机制以及毒性作用和副作用，需要进一步深入研究。一些已进入临床试验阶段（Defactinib（II期）、PF-562271（I期）、CEP-37440（I期）、PND-1186（I期）、GSK-2256098（II期）、BI-853520（I期）），为肺部疾病提供了潜在的治疗靶点。总体而言，这些发现为FAK抑制剂的研发奠定了基础。新兴方法，如PROTAC降解剂和联合治疗方案，在未来研究中显示出巨大潜力。基于对2015年至今相关文献的综合分析，本综述简要介绍了FAK的结构和功能，并讨论了FAK及其抑制剂在肺部疾病方面的最新研究进展。
