The KRAS signalling pathway is pivotal for pancreatic ductal adenocarcinoma (PDAC) development. After the failure of most conventional cytotoxic and targeted therapeutics tested so far, the combination of taxane nab-paclitaxel (Abraxane) with gemcitabine recently demonstrated promising improvements in the survival of PDAC patients. This study aimed to explore interactions of conventional paclitaxel and experimental taxane SB-T-1216 with the KRAS signalling pathway expression in in vivo and in vitro PDAC models in order to decipher potential predictive biomarkers or targets for future individualised therapy. Mouse PDAC PaCa-44 xenograft model was used for evaluation of changes in transcript and protein levels of the KRAS signalling pathway caused by administration of experimental taxane SB-T-1216 in vivo. Subsequently, KRAS wild-type (BxPc-3) and mutated (MiaPaCa-2 and PaCa-44) cell line models were treated with paclitaxel to verify dysregulation of the KRAS signalling pathway gene expression profile in vitro and investigate the role of KRAS mutation status. By comparing the gene expression profiles, this study observed for the first time that in vitro cell models differ in the basal transcriptional profile of the KRAS signalling pathway, but there were no differences between KRAS mutated and wild-type cells in sensitivity to taxanes. Generally, the taxane administration caused a downregulation of the KRAS signalling pathway both in vitro and in vivo, but this effect was not dependent on the KRAS mutation status. In conclusion, putative biomarkers for prediction of taxane activity or targets for stimulation of taxane anticancer effects were not discovered by the KRAS signalling pathway profiling in various PDAC models.

中文翻译：

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传统和实验紫杉烷类在胰腺癌模型中的KRAS通路表达变化。

KRAS信号通路对于胰腺导管腺癌（PDAC）的发展至关重要。在迄今为止测试的大多数常规细胞毒性和靶向治疗药物失败后，紫杉烷nab-紫杉醇（Abraxane）与吉西他滨的组合最近证明在PDAC患者的生存中有望实现改善。这项研究旨在探讨体内和体外PDAC模型中常规紫杉醇和实验紫杉烷SB-T-1216与KRAS信号通路表达的相互作用，从而为将来的个体化治疗解密潜在的预测性生物标志物或靶标。小鼠PDAC PaCa-44异种移植模型用于评估由体内施用实验紫杉烷SB-T-1216引起的KRAS信号通路的转录本和蛋白质水平的变化。后来，用紫杉醇处理KRAS野生型（BxPc-3）和突变（MiaPaCa-2和PaCa-44）细胞系模型，以验证体外KRAS信号通路基因表达谱的失调，并研究KRAS突变状态的作用。通过比较基因表达谱，这项研究首次观察到体外细胞模型在KRAS信号传导途径的基础转录谱方面存在差异，但在KRAS突变和野生型细胞之间对紫杉烷的敏感性没有差异。通常，紫杉烷的施用在体外和体内都引起KRAS信号通路的下调，但是这种作用并不取决于KRAS突变状态。结论，