Targeted Protein Degradation in Lung Cancer: The Emerging Role of PROTAC Technology and E3 Ligases

Abstract: Lung cancer remains one of the most prevalent and lethal malignancies, with poor drug response and high mortality rates. Proteolysis-targeting chimeras (PROTACs) are emerging as a novel therapeutic strategy, leveraging E3 ligases to degrade oncogenic proteins selectively via the ubiquitin-proteasome pathway. These degraders offer higher selectivity and bioavailability compared to traditional inhibitors. This review explores how PROTACs eliminate oncogenic proteins in lung cancer and examines the role of E3 ligases in this process. Commonly utilized ligases include Cereblon (CRBN) and Von Hippel-Lindau (VHL), while newer ones, such as MDM2 and Kelch-like ECH-associated protein 1 (KEAP1), are being investigated for therapeutic potential. We discuss key factors in PROTAC design, including ligand selection, linker optimization, and pharmacokinetic properties, which influence tumor specificity and efficacy while minimizing off- target effects. Additionally, we highlight targetable oncogenic drivers in lung cancer, such as KRAS, EGFR, and ALK fusion proteins, and evaluate preclinical and clinical studies that demonstrate PROTACs' potential for overcoming drug resistance. The challenges associated with clinical translation, tumor microenvironment interactions, and E3 ligase selection are also discussed. Finally, we present future perspectives, including expanding the range of E3 ligases, developing multitargeting strategies, and integrating next-generation molecular glue degraders. By offering a comparative analysis of E3 ligase- specific PROTACs, this review underscores the potential of PROTAC technology to advance precision oncology in lung cancer.