Targeting the Ubiquitin-Proteasome System: An Emerging Paradigm for Overcoming Resistance to Targeted Therapy in...

The introduction of tyrosine kinase inhibitors (TKIs) targeting driver oncogenes such as EGFR, ALK, and KRAS has substantially reshaped the treatment landscape of non-small cell lung cancer (NSCLC) and improved patient outcomes. However, inevitable acquired resistance remains the core obstacle to therapeutic success. Unlike previous studies that have largely focused on secondary mutations or bypass activation, the role of proteostasis imbalance in the evolution of resistance is increasingly recognized. The ubiquitin-proteasome system (UPS), as the central machinery for intracellular protein degradation and quality control, precisely regulates the stability, localization, and function of numerous key proteins, and is extensively involved in cell cycle progression, apoptosis, DNA damage repair, and various signaling pathways. Accumulating evidence indicates that UPS dysregulation is a critical factor in the emergence and maintenance of resistance to targeted therapy in NSCLC. By altering the expression and activity of specific E3 ligases or deubiquitinating enzymes (DUBs), resistant cells can remodel their proteome to achieve aberrant stabilization of pro-survival proteins, degradation of pro-apoptotic factors, or activation of alternative survival pathways, thereby adapting to TKI pressure. In light of this, developing interventions targeting core components of the UPS-such as next-generation proteasome inhibitors, molecular glues, PROTACs, and inhibitors of E3 ligases or DUBs-has emerged as a highly promising direction to overcome resistance. This review aims to systematically summarize the molecular mechanisms by which the UPS contributes to targeted therapy resistance in NSCLC, evaluate recent progress in emerging UPS-targeting strategies-most of which remain at preclinical or early clinical stages-and critically discuss the major barriers impeding their clinical translation, including off-target toxicity, selectivity issues, and the need for rationally designed combination regimens.