胰腺癌患者的生存率很低，经常使用吉西他滨 (Gem) 进行治疗。然而，最初的肿瘤敏感性常常让位于快速发展的耐药性。基于宝石的药物组合用于提高疗效和减轻耐药性，但我们对分子水平药物相互作用的理解有限，这有助于开发更有效的治疗方案。整体定量蛋白质组学分析可以为药物组合相互作用提供新的机制见解，但对药物组合研究通常所需的大样本集进行高质量的定量蛋白质组学分析具有挑战性。在这里，我们使用 IonStar（一种稳健的大规模蛋白质组学方法，采用良好控制的方法）在多个治疗组（N = 42 个样本）中研究了 Gem 与 BGJ398（infigratinib）（一种最近批准的泛 FGFR 抑制剂）的分子水平时间相互作用。 ，超高分辨率 MS1 定量。对样本集中总共 5514 个蛋白质进行了无缺失数据的定量，要求 >2 个独特肽/蛋白质、<1% 蛋白质错误发现率 (FDR)、<0.1% 肽 FDR 和 CV < 10%。对差异改变的蛋白质的功能分析揭示了药物失调的过程，例如代谢、细胞凋亡和抗原呈递途径。使用海马代谢测定和免疫测定对这些变化进行了实验验证。总体而言，对大规模蛋白质组学数据的深入分析为 FGFR 抑制剂补充和增强胰腺癌中 Gem 活性的可能机制提供了新的见解。

Pancreatic cancer patients have poor survival rates and are frequently treated using gemcitabine (Gem). However, initial tumor sensitivity often gives way to rapid development of resistance. Gem-based drug combinations are employed to increase efficacy and mitigate resistance, but our understanding of molecular-level drug interactions, which could assist in the development of more effective therapeutic regimens, is limited. Global quantitative proteomic analysis could provide novel mechanistic insights into drug combination interactions, but it is challenging to achieve high-quality quantitative proteomics analysis of the large sample sets that are typically required for drug combination studies. Here, we investigated molecular-level temporal interactions of Gem with BGJ398 (infigratinib), a recently approved pan-FGFR inhibitor, in multiple treatment groups (N = 42 samples) using IonStar, a robust large-scale proteomics method that employs well-controlled, ultrahigh-resolution MS1 quantification. A total of 5514 proteins in the sample set were quantified without missing data, requiring >2 unique peptides/protein, <1% protein false discovery rate (FDR), <0.1% peptide FDR, and CV < 10%. Functional analysis of the differentially altered proteins revealed drug-dysregulated processes such as metabolism, apoptosis, and antigen presentation pathways. These changes were validated experimentally using Seahorse metabolic assays and immunoassays. Overall, in-depth analysis of large-scale proteomics data provided novel insights into possible mechanisms by which FGFR inhibitors complement and enhance Gem activity in pancreatic cancers.