Exploiting E3 ligases for lung cancer therapy: The promise of DCAF-PROTACs

Lung cancer remains the leading cause of cancer-related mortality, underscoring the urgent need for novel therapeutic strategies. One emerging approach in drug development targets oncogenic proteins via the ubiquitin-proteasome system (UPS), specifically through proteolysis-targeting chimeras (PROTACs). Among the various E3 ligase complexes, the CRL4 complex—comprising DDB1 and CUL4-associated factors (DCAFs)—has garnered attention for its roles in cellular homeostasis, DNA repair, and oncogenesis. This review explores the therapeutic potential of DCAF-based PROTACs (DCAF-PROTACs) in lung cancer by focusing on the substrate receptors DCAF13, DCAF15, and DCAF16, which mediate CRL4-dependent ubiquitination. We first discuss the dysregulation of DCAF proteins in lung cancer and then elaborate on their mechanistic role in facilitating target-specific protein degradation via DCAF-E3 ligase complexes. Recent studies show that DCAF-PROTACs selectively degrade oncogenic proteins, addressing treatment resistance and tumor heterogeneity. Notably, DCAF13 promotes lung adenocarcinoma by destabilizing p53, while DCAF15-PROTACs target and degrade RBM39 effectively. Additionally, the development of electrophilic PROTACs targeting DCAF16 presents a promising avenue for degrading nuclear proteins. Despite these advancements, several challenges must be addressed prior to clinical translation, including issues related to drug bioavailability, stability, and emerging resistance mechanisms. This review also explores the potential of combination therapies, particularly with immunotherapy, to enhance tumor specificity and therapeutic efficacy. Ultimately, the deployment of DCAF-PROTACs marks a significant advancement in precision oncology, offering a novel and targeted approach to protein degradation-based cancer treatment.