Reduced Efficacy of the Plk1 Inhibitor BI 2536 on the Progression of Hepatocellular Carcinoma due to Low Intratumoral Drug Levels
Reduced Efficacy of the Plk1 Inhibitor BI 2536 on the Progression of Hepatocellular Carcinoma due to Low Intratumoral Drug Levels
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DOI：
10.1596/neo.111366
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发表时间：
2012-05-01
期刊：
影响因子：
4.8
通讯作者：
Piiper, Albrecht
中科院分区：
文献类型：
--
作者：
Haupenthal, Jorg;Bihrer, Verena;Piiper, Albrecht
在培养细胞和异种移植裸鼠中获得的非常有前景的临床前数据与 Polo 样激酶 1 (Plk1) 抑制剂相当有限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，以及良好反映自然发生癌症的肿瘤细胞和微环境特征的基因工程小鼠肿瘤模型是否适合研究抗 Plk1 疗法。对人类 HCC 样本中 Plk1 表达的分析证实，HCC 表达的 Plk1 水平远高于邻近正常肝组织。编码针对 Plk1 的短发夹 RNA 的腺病毒或小分子抑制剂 BI 2536 对 Plk1 的抑制可降低 HCC 细胞系的活力，并抑制裸鼠中 HCC 异种移植物的进展。在肝癌发生过程中，使用 BI 2536 治疗转化生长因子 (TGF) α/c-myc 双转基因小鼠可减少异常增生病灶和病灶内 Ki-67 阳性细胞的数量，表明肿瘤发生减少。相比之下，磁共振成像显示，BI 2536 对转基因小鼠 HCC 模型中的 HCC 进展没有显着影响。通过质谱法测量 BI 2536 显示，与邻近的正常肝组织相比，HCC 中的 BI 2536 水平显着降低。总之，低肿瘤内水平是 Plk1 抑制剂 BI 2536 耐药的新机制。达到足够肿瘤内水平的 Plk1 抑制剂在 HCC 治疗中非常有前景。肿瘤 (2012) 14, 410-419
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 microenvironmental 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) alpha/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. Neoplasia (2012) 14, 410-419