Department of Medicine I, Johann Wolfgang Goethe University, Frankfurt, Germany.
Neoplasia. 2012 May;14(5):410-9. doi: 10.1596/neo.111366.
Highly promising preclinical data obtained in cultured cells and in nude mice bearing xenografts contrast with the rather modest clinical efficacy of Polo-like kinase 1 (Plk1) inhibitors. In the present study, we investigated if Plk1 might be a suitable target in hepatocellular carcinoma (HCC) and if a genetically engineered mouse tumor model that well reflects the tumor cell and micro-environmental features of naturally occurring cancers might be suitable to study anti-Plk1 therapy. Analysis of Plk1 expression in human HCC samples confirmed that HCC express much higher Plk1 levels than the adjacent normal liver tissue. Inhibition of Plk1 by an adenovirus encoding for a short hairpin RNA against Plk1 or by the small-molecule inhibitor BI 2536 reduced the viability of HCC cell lines and inhibited HCC xenograft progression in nude mice. Treatment of transforming growth factor (TGF) α/c-myc bitransgenic mice with BI 2536 during hepatocarcinogenesis reduced the number of dysplastic foci and of Ki-67-positive cells within the foci, indicating diminished tumorigenesis. In contrast, BI 2536 had no significant effect on HCC progression in the transgenic mouse HCC model as revealed by magnetic resonance imaging. Measurement of BI 2536 by mass spectrometry revealed considerably lower BI 2536 levels in HCC compared with the adjacent normal liver tissue. In conclusion, low intratumoral levels are a novel mechanism of resistance to the Plk1 inhibitor BI 2536. Plk1 inhibitors achieving sufficient intratumoral levels are highly promising in HCC treatment.
在培养细胞和异种移植裸鼠中获得的极具前景的临床前数据与 Polo 样激酶 1（Plk1）抑制剂的相当温和的临床疗效形成鲜明对比。在本研究中，我们研究了 Plk1 是否可能是肝细胞癌（HCC）的合适靶点，以及是否存在一种遗传工程小鼠肿瘤模型，该模型能很好地反映自然发生的癌症的肿瘤细胞和微环境特征，从而适合研究抗 Plk1 治疗。对人 HCC 样本中 Plk1 表达的分析证实，HCC 表达的 Plk1 水平远高于相邻的正常肝组织。通过表达 Plk1 的短发夹 RNA 的腺病毒或小分子抑制剂 BI 2536 抑制 Plk1，可降低 HCC 细胞系的活力，并抑制裸鼠异种移植肿瘤的进展。在肝癌发生过程中，用 BI 2536 治疗转化生长因子（TGF）α/c-myc 双转基因小鼠可减少异型焦点的数量和焦点内的 Ki-67 阳性细胞，表明肿瘤发生减少。相比之下，BI 2536 对转基因小鼠 HCC 模型中的 HCC 进展没有显著影响，这一点通过磁共振成像揭示。通过质谱法测量 BI 2536 发现，与相邻的正常肝组织相比，HCC 中的 BI 2536 水平明显较低。总之，肿瘤内水平低是对 Plk1 抑制剂 BI 2536 产生耐药性的新机制。达到足够肿瘤内水平的 Plk1 抑制剂在 HCC 治疗中极具前景。
