Increased basal protein synthesis activity is a hallmark feature that distinguishes many types of malignant cells from their normal counterparts. The survival and proliferation of cancer cells are tightly linked to functional unfolded protein response (UPR) and endoplasmic reticulum (ER)-associated degradation (ERAD) pathways due to their high rates of protein synthesis. The evolutionarily conserved AAA+ ATPase valosin-containing protein (VCP)/p97 facilitates the extraction of proteins from organelles, chromatin, and protein complexes to target them for ubiquitin–proteasome system (UPS)-mediated degradation. p97 plays a key role in protein quality control and in the maintenance of protein homeostasis through its regulation of ERAD. The disruption of p97 activity leads to an accumulation of undegraded proteins, triggers the UPR, and can culminate in proteotoxic cell death. Given this, p97 inhibition offers an opportunity to selectively kill cancer cells that exhibit high basal protein synthesis rates. This review explores p97’s molecular structure, diverse cellular roles, and clinical potential with a particular focus on CB-5083 and CB-5339, the only p97 inhibitors to date that have advanced into clinical trials. We discuss their mechanisms of action, clinical trial outcomes, and the transformative potential of rational combination strategies to maximize their therapeutic potential. By integrating foundational biological insights with translational perspectives, we highlight p97 as a precision target for cancer treatment.
基础蛋白质合成活性增强是区分多种恶性细胞与其正常对应细胞的一个标志性特征。由于癌细胞蛋白质合成速率较高，其存活和增殖与功能性未折叠蛋白反应（UPR）及内质网相关降解（ERAD）通路紧密相关。进化上保守的AAA+ ATP酶含缬酪肽蛋白（VCP）/p97通过促进蛋白质从细胞器、染色质及蛋白质复合物中提取，将其靶向泛素-蛋白酶体系统（UPS）介导的降解过程。p97通过调控ERAD，在蛋白质质量控制和维持蛋白质稳态中发挥关键作用。p97活性破坏会导致未降解蛋白质积累，触发UPR，并最终可能导致蛋白毒性细胞死亡。鉴于此，抑制p97为选择性杀灭具有高基础蛋白质合成速率的癌细胞提供了可能。本综述探讨了p97的分子结构、多样化的细胞功能及临床潜力，特别聚焦于迄今唯一进入临床试验阶段的p97抑制剂CB-5083和CB-5339。我们讨论了其作用机制、临床试验结果，以及通过合理联合策略最大化其治疗潜力的变革性前景。通过整合基础生物学见解与转化医学视角，我们强调p97可作为癌症治疗的精准靶点。
Harnessing p97/VCP: A Transformative AAA+ ATPase Target for Next-Generation Cancer Therapeutics
肿瘤(癌症)患者之家