Van Andel Research Institute, Grand Rapids, MI, USA.
Cancer Res. 2011 Aug 1;71(15):5225-34. doi: 10.1158/0008-5472.CAN-11-0076. Epub 2011 Jun 3.
In recent years, several molecularly targeted therapies have been approved for clear cell renal cell carcinoma (ccRCC), a highly aggressive cancer. Although these therapies significantly extend overall survival, nearly all patients with advanced ccRCC eventually succumb to the disease. To identify other molecular targets, we profiled gene expression in 90 ccRCC patient specimens for which tumor grade information was available. Gene set enrichment analysis indicated that cell-cycle-related genes, in particular, Polo-like kinase 1 (PLK1), were associated with disease aggressiveness. We also carried out RNAi screening to identify kinases and phosphatases that when inhibited could prevent cell proliferation. As expected, RNAi-mediated knockdown of PLK1 and other cell-cycle kinases was sufficient to suppress ccRCC cell proliferation. The association of PLK1 in both disease aggression and in vitro growth prompted us to examine the effects of a small-molecule inhibitor of PLK1, BI 2536, in ccRCC cell lines. BI 2536 inhibited the proliferation of ccRCC cell lines at concentrations required to inhibit PLK1 kinase activity, and sustained inhibition of PLK1 by BI 2536 led to dramatic regression of ccRCC xenograft tumors in vivo. Taken together, these findings highlight PLK1 as a rational therapeutic target for ccRCC.
近年来，已有几种针对透明细胞肾细胞癌（ccRCC）的分子靶向疗法获得批准，透明细胞肾细胞癌是一种侵袭性很强的癌症。尽管这些疗法显著延长了总生存期，但几乎所有晚期 ccRCC 患者最终都会死于该疾病。为了寻找其他分子靶点，我们对 90 份 ccRCC 患者标本进行了基因表达谱分析，这些标本均有肿瘤分级信息。基因集富集分析表明，细胞周期相关基因，特别是 Polo 样激酶 1（PLK1），与疾病侵袭性相关。我们还进行了 RNAi 筛选，以鉴定出受抑制后可阻止细胞增殖的激酶和磷酸酶。不出所料，RNAi 介导的 PLK1 和其他细胞周期激酶的敲低足以抑制 ccRCC 细胞的增殖。PLK1 与疾病侵袭性和体外生长的关联促使我们研究了 PLK1 的小分子抑制剂 BI 2536 在 ccRCC 细胞系中的作用。BI 2536 以抑制 PLK1 激酶活性所需的浓度抑制 ccRCC 细胞系的增殖，持续抑制 PLK1 可导致体内 ccRCC 异种移植肿瘤的显著消退。综上所述，这些发现凸显了 PLK1 作为 ccRCC 的合理治疗靶点。
