FAK and PYK2 As Central Resistance Nodes in Non-Small Cell Lung Cancer: Signalling Crosstalk and Combination Therapeutic Strategies

Introduction: Non-Small Cell Lung Cancer (NSCLC) remains a major clinical challenge and is one of the leading causes of cancer-related mortality worldwide. Its poor prognosis is driven by substantial molecular heterogeneity, dynamic interactions between tumor cells and the surrounding microenvironment, and the frequent development of therapeutic resistance. Among the signaling pathways involved, Focal Adhesion Kinase (FAK) and Proline-rich tyrosine Kinase 2 (PYK2) have emerged as important regulators that integrate oncogenic and microenvironmental signals, thereby promoting tumor progression and resistance to therapy. Methods: A narrative literature review was conducted using major scientific databases to evaluate the mechanistic, preclinical, and clinical evidence regarding the role of FAK/PYK2 signaling in NSCLC. Studies investigating pathway interactions, mechanisms of therapeutic resistance, combination treatment strategies, and nanocarrier-mediated drug delivery systems were critically analyzed. Results: FAK and PYK2 function as central signaling hubs that connect key oncogenic pathways, including Epidermal Growth Factor Receptor (EGFR), Phosphoinositide 3-Kinase/Protein Kinase B (PI3K/AKT), Mitogen-Activated Protein Kinase (MAPK), and Janus Kinase/Signal Transducer and Activator of Transcription (JAK/STAT) signaling. Activation of these kinases promotes cell proliferation, survival, epithelial–mesenchymal transition, and therapeutic resistance. Although FAK/PYK2-targeted monotherapy has demonstrated limited clinical efficacy, rational combination strategies involving EGFR tyrosine kinase inhibitors, MAPK inhibitors, chemotherapy, or immunotherapy have shown promising synergistic effects. In addition, nanocarrier-based delivery systems may improve drug targeting and pharmacokinetic profiles while reducing systemic toxicity. Discussion: The adaptive quality of the disease calls for multi-pathway therapeutic strategies for the treatment of NSCLC. Blocking FAK/PYK2 may interrupt the integrated signaling pathways and compensatory mechanisms that contribute to resistance. Precision-guided combination regimens aided by the use of biomarker-driven patient selection are critical when it comes to improving clinical outcomes. Conclusion: FAK and PYK2 represent promising therapeutic targets in NSCLC. Strategies involving multi-pathway inhibition and advanced drug delivery platforms offer a rational approach to suppress tumor growth and overcome therapeutic resistance. Further investigation in translational and clinical settings is warranted to establish their therapeutic potential.