Division of Medical Oncology, Department of Medicine, University of Colorado Cancer Center, Aurora, CO 80045, USA.
Clin Cancer Res. 2013 Jan 1;19(1):291-303. doi: 10.1158/1078-0432.CCR-12-1611. Epub 2012 Nov 7.
The Aurora kinases are a family of conserved serine-threonine kinases with key roles in mitotic cell division. As with other promising anticancer targets, patient selection strategies to identify a responsive subtype will likely be required for successful clinical development of Aurora kinase inhibitors. The purpose of this study was to evaluate the antitumor activity of the Aurora and angiogenic kinase inhibitor ENMD-2076 against preclinical models of breast cancer with identification of candidate predictive biomarkers.
Twenty-nine breast cancer cell lines were exposed to ENMD-2076 and the effects on proliferation, apoptosis, and cell-cycle distribution were evaluated. In vitro activity was confirmed in MDA-MB-468 and MDA-MB-231 triple-negative breast cancer xenografts. Systematic gene expression analysis was used to identify up- and downregulated pathways in the sensitive and resistant cell lines, including within the triple-negative breast cancer subset.
ENMD-2076 showed antiproliferative activity against breast cancer cell lines, with more robust activity against cell lines lacking estrogen receptor expression and those without increased HER2 expression. Within the triple-negative breast cancer subset, cell lines with a p53 mutation and increased p53 expression were more sensitive to the cytotoxic and proapoptotic effects of ENMD-2076 exposure than cell lines with decreased p53 expression.
ENMD-2076 exhibited robust anticancer activity against models of triple-negative breast cancer and the candidate predictive biomarkers identified in this study may be useful in selecting patients for Aurora kinase inhibitors in the future.
极光激酶是一组保守的丝氨酸/苏氨酸激酶，在有丝分裂细胞分裂中起关键作用。与其他有前途的抗癌靶点一样，为了成功开发极光激酶抑制剂的临床应用，可能需要制定患者选择策略来识别反应性亚型。本研究的目的是评估 Aurora 和血管生成激酶抑制剂 ENMD-2076 针对乳腺癌临床前模型的抗肿瘤活性，并确定候选预测性生物标志物。
将 29 种乳腺癌细胞系暴露于 ENMD-2076 中，并评估其对增殖、凋亡和细胞周期分布的影响。在 MDA-MB-468 和 MDA-MB-231 三阴性乳腺癌异种移植模型中证实了体外活性。系统的基因表达分析用于鉴定敏感和耐药细胞系中的上调和下调途径，包括三阴性乳腺癌亚组中的途径。
ENMD-2076 对乳腺癌细胞系表现出抗增殖活性，对缺乏雌激素受体表达和 HER2 表达增加的细胞系的活性更强。在三阴性乳腺癌亚组中，与 p53 表达降低的细胞系相比，p53 突变和 p53 表达增加的细胞系对 ENMD-2076 暴露的细胞毒性和促凋亡作用更为敏感。
ENMD-2076 对三阴性乳腺癌模型表现出强大的抗肿瘤活性，本研究中确定的候选预测性生物标志物可能有助于将来选择极光激酶抑制剂的患者。
