PROTAC-induced protein degradation in lung cancer

Lung cancer, the leading cause of cancer-related mortality worldwide, remains a formidable therapeutic challenge due to profound tumor heterogeneity and the emergence of drug resistance. Conventional small-molecule inhibitors that rely on an occupancy-driven mechanism are frequently undermined by acquired mutations. Proteolysis-targeting chimeras (PROTACs) represent an event-driven therapeutic strategy that enables catalytic degradation of disease-driving proteins. This review systematically summarizes recent advances in PROTAC technology for lung cancer, emphasizing its efficacy against key oncogenic drivers (e.g., EGFR, KRAS, ALK, MET) and reactivating apoptosis (e.g., via B-cell lymphoma [BCL]-2/BCL-extra-large [BCL-2/BCL-xL] degrader 753b). We further highlight potential applications targeting epigenetic regulators such as bromodomain protein 4 (BRD4) to overcome immunosuppression via programmed death ligand-1 degradation. Despite promising preclinical results, the clinical translation of PROTACs faces challenges in pharmacokinetics, tissue specificity, and resistance. Finally, we discuss emerging innovations such as next-generation degraders and advanced delivery strategies, including antibody-PROTAC conjugates (Ab-PROTACs) and nano-PROTACs, underscoring PROTACs' potential to redefine precision oncology in lung cancer.