Clinical Translational Research Division, Translational Genomic Research Institute (TGen), 13208 E Shea Blvd, Scottsdale, AZ 85259, USA.
Biochem Pharmacol. 2012 Feb 15;83(4):452-61. doi: 10.1016/j.bcp.2011.11.005. Epub 2011 Nov 15.
Aurora kinases are a family of mitotic kinases that play important roles in the tumorigenesis of a variety of cancers including pancreatic cancer. A number of Aurora kinase inhibitors (AKIs) are currently being tested in preclinical and clinical settings as anti-cancer therapies. However, the antitumor activity of AKIs in clinical trials has been modest. In order to improve the antitumor activity of AKIs in pancreatic cancer, we utilized a kinome focused RNAi screen to identify genes that, when silenced, would sensitize pancreatic cancer cells to AKI treatment. A total of 17 kinase genes were identified and confirmed as positive hits. One of the hits was the platelet-derived growth factor receptor, alpha polypeptide (PDGFRA), which has been shown to be overexpressed in pancreatic cancer cells and tumor tissues. Imatinib, a PDGFR inhibitor, significantly enhanced the anti-proliferative effect of ZM447439, an Aurora B specific inhibitor, and PHA-739358, a pan-Aurora kinase inhibitor. Further studies showed that imatinib augmented the induction of G2/M cell cycle arrest and apoptosis by PHA-739358. These findings indicate that PDGFRA is a potential mediator of AKI sensitivity in pancreatic cancer cells.
极光激酶是一类有丝分裂激酶，在包括胰腺癌在内的多种癌症的肿瘤发生中发挥重要作用。目前有许多极光激酶抑制剂（AKI）正在临床前和临床环境中作为抗癌疗法进行测试。然而，AKI 在临床试验中的抗肿瘤活性一直较为温和。为了提高 AKI 在胰腺癌中的抗肿瘤活性，我们利用一个激酶组聚焦的 RNAi 筛选来鉴定那些在沉默时会使胰腺癌细胞对 AKI 治疗敏感的基因。总共鉴定并确认了 17 个激酶基因作为阳性命中。其中一个命中是血小板衍生生长因子受体，α多肽（PDGFRA），它在胰腺癌细胞和肿瘤组织中过度表达。伊马替尼，一种 PDGFR 抑制剂，显著增强了 Aurora B 特异性抑制剂 ZM447439 和泛 Aurora 激酶抑制剂 PHA-739358 的抗增殖作用。进一步的研究表明，伊马替尼增强了 PHA-739358 诱导的 G2/M 细胞周期阻滞和凋亡。这些发现表明 PDGFRA 是胰腺癌细胞对 AKI 敏感性的潜在介质。
