PROTAC-induced protein degradation in lung cancer

Abstract

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.