Targeting Focal Adhesion Kinase in Lung Diseases: Current Progress and Future Directions

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.