Purpose

Oncogenic KRAS mutations are found in over 90% of pancreatic ductal adenocarcinomas (PDACs). As yet, however, no effective therapies are available for KRAS-induced malignancies. Therefore, research aimed at the identification of KRAS targets with therapeutic potential is warranted. Our goal was to investigate Aurora A (AURKA) and targeting protein for Xklp2 (TPX2) as potential therapeutic targets in PDAC.

Methods

AURKA and TPX2 expression was assessed using RNAseq and qRT-PCR in PDAC patient samples and matched non-tumor pancreatic tissues. Publicly available PDAC datasets were used to investigate associations of AURKA and TPX2 expression levels with patient survival and the presence of KRAS mutations. Next, we used an Aurora kinase inhibitor, or KRAS, AURKA and TPX2 targeting using RNA interference in KRAS-mutant PDAC cells and, subsequently, analyzed their clonogenic and anchorage-independent growth and migration.

Results

We found that relative to matched non-tumor tissues, PDAC tumors displayed significantly higher expression levels of AURKA and TPX2. In addition, we found that AURKA and TPX2 were co-expressed in PDAC datasets, and that high expression levels of AURKA and TPX2 were associated with a shorter patient survival and with the presence of oncogenic KRAS mutations. In addition, we found that siRNA-mediated KRAS targeting in KRAS-mutant PDAC cells reduced AURKA and TPX2 expression. Furthermore, targeting AURKA or TPX2 in KRAS-mutant PDAC cells reduced their clonogenic and anchorage-independent growth, as well their migration.

Conclusions

From our data we conclude that AURKA and TPX2 may act as KRAS biomarkers in PDAC that can predict a worse prognosis, and that AURKA or TPX2 targeting in PDAC cells may reduce their transformed phenotype. These results indicate that AURKA and TPX2 may serve as promising targets to be explored for KRAS-mutant PDAC therapy.

中文翻译：

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Aurora A激酶及其激活物TPX2是KRAS诱导的胰腺癌的潜在治疗靶标。

目的

在超过90％的胰腺导管腺癌（PDAC）中发现了致癌性KRAS突变。然而，到目前为止，还没有有效的疗法可用于KRAS诱发的恶性肿瘤。因此，有必要进行旨在鉴定具有治疗潜力的KRAS靶标的研究。我们的目标是研究Aurora A（AURKA）和Xklp2（TPX2）的靶向蛋白作为PDAC中的潜在治疗靶标。

方法

使用RNAseq和qRT-PCR在PDAC患者样品和匹配的非肿瘤胰腺组织中评估AURKA和TPX2表达。使用公开可用的PDAC数据集来研究AURKA和TPX2表达水平与患者生存率和KRAS突变的存在之间的关系。接下来，我们在KRAS突变型PDAC细胞中使用Aurora激酶抑制剂或KRAS，AURKA和TPX2，并利用RNA干扰进行靶向，随后分析了它们的克隆形成和锚定非依赖性生长和迁移。

结果

我们发现相对于匹配的非肿瘤组织，PDAC肿瘤表现出明显更高的AURKA和TPX2表达水平。此外，我们发现AURKA和TPX2在PDAC数据集中共表达，而AURKA和TPX2的高表达水平与患者生存期较短和致癌性KRAS突变有关。此外，我们发现在KRAS突变的PDAC细胞中siRNA介导的KRAS靶向降低了AURKA和TPX2的表达。此外，在KRAS突变的PDAC细胞中靶向AURKA或TPX2减少了它们的克隆形成和锚定非依赖性生长，以及它们的迁移。

结论

根据我们的数据，我们得出结论，AURKA和TPX2可能在PDAC中充当KRAS生物标志物，可以预测更坏的预后，而在PDAC细胞中靶向AURKA或TPX2可能会降低其转化表型。这些结果表明，AURKA和TPX2可以作为有希望的靶点，用于KRAS突变PDAC治疗。