Hussain Md Sadique, Eltaib Lina, Rana Amita Joshi, Maqbool Mudasir, Ashique Sumel, Alanazi Mashael N, Khan Yumna, Agrawal Mohit
Uttaranchal Institute of Pharmaceutical Sciences, Uttaranchal University, Prem Nagar, Dehradun, Uttarakhand 248007, India.
Department of Pharmaceutics, College of Pharmacy, Northern Border University, Rafha, Saudi Arabia.
Pathol Res Pract. 2025 Jun;270:156001. doi: 10.1016/j.prp.2025.156001. Epub 2025 May 10.
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.
肺癌仍然是癌症相关死亡的主要原因，这凸显了对新型治疗策略的迫切需求。药物开发中一种新兴的方法是通过泛素-蛋白酶体系统（UPS）靶向致癌蛋白，特别是通过蛋白酶靶向嵌合体（PROTAC）。在各种E3连接酶复合物中，由损伤特异性DNA结合蛋白1（DDB1）和CUL4相关因子（DCAF）组成的CRL4复合物因其在细胞稳态、DNA修复和肿瘤发生中的作用而受到关注。本综述通过聚焦介导CRL4依赖性泛素化的底物受体DCAF13、DCAF15和DCAF16，探讨了基于DCAF的PROTAC（DCAF-PROTAC）在肺癌中的治疗潜力。我们首先讨论肺癌中DCAF蛋白的失调，然后详细阐述它们通过DCAF-E3连接酶复合物促进靶标特异性蛋白降解的机制作用。最近的研究表明，DCAF-PROTAC选择性降解致癌蛋白，解决治疗耐药性和肿瘤异质性问题。值得注意的是，DCAF13通过使p53不稳定来促进肺腺癌，而DCAF15-PROTAC有效地靶向并降解RBM39。此外，开发靶向DCAF16的亲电PROTAC为降解核蛋白提供了一条有前景的途径。尽管取得了这些进展，但在临床转化之前必须解决几个挑战，包括与药物生物利用度、稳定性和新出现的耐药机制相关的问题。本综述还探讨了联合疗法的潜力，特别是与免疫疗法联合，以提高肿瘤特异性和治疗效果。最终，DCAF-PROTAC的应用标志着精准肿瘤学的重大进展，为基于蛋白降解的癌症治疗提供了一种新颖且有针对性的方法。
