Abstract：
KRAS-mutant cancers, due to their protein targeting complexity, present significant therapeutic hurdles. The identification of the macropinocytic phenotype in these cancers has emerged as a promising alternative therapeutic target. Our study introduces MPD1, an macropinocytosis-targeting peptide-drug conjugates (PDC), which is developed to treat KRAS mutant cancers. This PDC is specifically designed to trigger a positive feedback loop through its caspase-3 cleavable characteristic. However, we observe that this loop is hindered by DNA-PK mediated DNA damage repair processes in cancer cells. To counter this impediment, we employ AZD7648, a DNA-PK inhibitor. Interestingly, the combined treatment of MPD1 and AZD7648 resulted in a 100% complete response rate in KRAS-mutant xenograft model. We focus on the synergic mechanism of it. We discover that AZD7648 specifically enhances macropinocytosis in KRAS-mutant cancer cells. Further analysis uncovers a significant correlation between the increase in macropinocytosis and PI3K signaling, driven by AMPK pathways. Also, AZD7648 reinforces the positive feedback loop, leading to escalated apoptosis and enhanced payload accumulation within tumors. AZD7648 possesses broad applications in augmenting nano-sized drug delivery and preventing DNA repair resistance. The promising efficacy and evident synergy underscore the potential of combining MPD1 with AZD7648 as a strategy for treating KRAS-mutant cancers.
摘要：
KRAS突变癌症,由于它们的蛋白质靶向复杂性，目前显著的治疗障碍。鉴定这些癌症中的巨噬细胞表型已成为有希望的替代治疗靶标。我们的研究介绍了MPD1，一种针对巨噬细胞吞噬的靶向肽-药物偶联物（PDC），用于治疗KRAS突变癌症。该PDC被特别设计为通过其半胱天冬酶-3可切割特性触发正反馈回路。然而,我们观察到，在癌细胞中，DNA-PK介导的DNA损伤修复过程阻碍了该环。为了克服这个障碍，我们使用AZD7648，一种DNA-PK抑制剂。有趣的是,在KRAS突变异种移植模型中,MPD1和AZD7648联合治疗的完全缓解率达到100%.我们专注于它的协同机制。我们发现AZD7648在KRAS突变的癌细胞中特异性增强巨成细胞作用。进一步的分析揭示了巨噬细胞增多和PI3K信号之间的显著相关性，由AMPK途径驱动。此外，AZD7648加强了正反馈回路，导致升级的细胞凋亡和增强的有效载荷在肿瘤内的积累。AZD7648在增强纳米大小的药物递送和防止DNA修复抗性方面具有广泛的应用。有希望的功效和明显的协同作用强调了将MPD1与AZD7648组合作为治疗KRAS突变癌症的策略的潜力。
