METHODS: We reanalyzed publicly available RNA-seq gene expression profiles of 28 PDAC patient-derived xenograft (PDX) models before and after a 21-day gemcitabine treatment using our validated analysis pipeline to identify molecular markers of intrinsic and acquired resistance.
RESULTS: Using normalized RNA-seq quantification measurements, we first identified oxidative phosphorylation and interferon alpha pathways as the two most enriched cancer hallmark gene sets in the baseline gene expression profile associated with intrinsic gemcitabine resistance and sensitivity, respectively. Furthermore, we discovered strong correlations between drug-induced expression changes in glycolysis and oxidative phosphorylation genes and response to gemcitabine, which suggests that these pathways may be associated with acquired gemcitabine resistance mechanisms. Thus, we developed prediction models using baseline gene expression profiles in those pathways and validated them in another dataset of 12 PDAC models from Novartis. We also developed prediction models based on drug-induced expression changes in genes from the Molecular Signatures Database (MSigDB)\'s curated 50 cancer hallmark gene sets. Finally, pathogenic TP53 mutations correlated with treatment resistance.
CONCLUSIONS: Our results demonstrate that concurrent upregulation of both glycolysis and oxidative phosphorylation pathways occurs in vivo in PDAC PDXs following gemcitabine treatment and that pathogenic TP53 status had association with gemcitabine resistance in these models. Our findings may elucidate the molecular basis for gemcitabine resistance and provide insights for effective drug combination in PDAC chemotherapy.
方法:我们在吉西他滨治疗21天之前和之后,重新分析了28例PDAC患者来源的异种移植(PDX)模型的公开RNA-seq基因表达谱。
结果:使用归一化RNA-seq定量测量,我们首先确定氧化磷酸化和干扰素α途径是与固有吉西他滨抗性和敏感性相关的基线基因表达谱中两个最丰富的癌症标志基因集。分别。此外,我们发现药物诱导的糖酵解和氧化磷酸化基因的表达变化与吉西他滨的反应之间存在很强的相关性,这表明这些途径可能与获得性吉西他滨耐药机制有关。因此,我们使用这些通路中的基线基因表达谱建立了预测模型,并在诺华的12个PDAC模型的另一个数据集中进行了验证.我们还开发了基于分子特征数据库(MSigDB)精选的50个癌症标志基因集的药物诱导基因表达变化的预测模型。最后,致病性TP53突变与治疗耐药相关。
结论:我们的结果表明,在吉西他滨治疗后,PDACPDX体内糖酵解和氧化磷酸化途径同时上调,并且在这些模型中,致病性TP53状态与吉西他滨耐药有关。我们的发现可以阐明吉西他滨耐药的分子基础,并为PDAC化疗中的有效药物组合提供见解。