Targeting focal adhesion kinase (FAK) in non-small cell lung cancer (NSCLC): Molecular mechanisms and combination therapeutic strategies.

Owing to the lack of obvious early symptoms, most patients are diagnosed with non-small cell lung cancer (NSCLC) at advanced stages and miss the optimal window for surgical intervention, which limits treatment options. In recent years, with the advancement of research into the pathogenesis of NSCLC, numerous targeted inhibitors, such as those targeting epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), and mesenchymal epithelial transition factor (MET), have been developed for the treatment of NSCLC. Nevertheless, resistance to these agents has been observed to varying extents. An increasing number of studies have confirmed that focal adhesion kinase (FAK) has emerged as a key research focus because of its crucial role in NSCLC initiation, progression and resistance. Several FAK-targeted inhibitors have advanced into clinical evaluation; for example, CEP-37440 is undergoing phase I trials, whereas GSK-2256098 has reached phase II trials. However, the therapeutic efficacy of monotherapy remains suboptimal. Therefore, the combination of FAK inhibitors with other treatment modalities, such as chemotherapy, targeted therapy, and immunotherapy, has become a promising direction for research. An increasing body of preclinical evidence supports the notion that FAK inhibitors, when used in combination with other therapies, exhibit enhanced and reliable efficacy against NSCLC. This review summarizes the structure and functional characteristics of FAK, its role in the pathogenesis of NSCLC, the research progress on FAK inhibitors, and the current status and prospects of combining FAK inhibitors with other therapies for NSCLC. The aim is to provide new insights for future clinical trial design and combination therapy strategies for NSCLC.