科研之友
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摘要
Aurora kinases are key regulators of mitotic events. Dysfunction of these kinases can cause polyploidy and chromosomal instability, a contributor to tumorigenesis. MK-5108 is a potent inhibitor of Aurora A kinase that has shown preclinical potent activity in malignancies of breast, cervical, colon, ovarian, and pancreatic origin. We sought to assess the preclinical efficacy of MK-5108 in a panel of non-small-cell lung cancer cell lines as a single agent and in combination with cisplatin and docetaxel. Eleven lung cancer cell lines were studied. Growth inhibition by MK-5108 was assessed with short- and long-term MTT assays. Cell cycling was measured by flow cytometry. Immunoblotting was used to determine targeted activity of MK-5108 on Aurora A and downstream effects (TACC3 and Plk1). Efficacy of combination studies performed with cisplatin and docetaxel was evaluated by median effect analysis. All cell lines demonstrated sustained growth inhibition following MK-5108 at varying nanomolar concentrations. MK-5108 induced G2/M accumulation, polyploidy, and apoptosis (increased sub-G1/PARP cleavage). Levels of Aurora A, TACC3, and Plk1 diminished. Concurrent treatment of MK-5108 with cisplatin or docetaxel synergistically inhibited cell growth with the docetaxel combination performing better. When administered sequentially, treatment with docetaxel first followed by MK-5108 exhibited greater growth inhibition than the inverse; yet concurrent treatment remained superior. MK-5108 has potent anti-proliferative activity in lung cancer cell lines alone and in combination with chemotherapies. Determining how best to integrate Aurora inhibitors into current lung cancer treatment regimens would be beneficial.
- 出版日期2014-7
