Anticancer activity of the Aurora A kinase inhibitor MK-5108 in non-small-cell lung cancer (NSCLC) in vitro as monotherapy and in combination with chemotherapies.

Danielle C Chinn, William S Holland, Philip C Mack

Journal of cancer research and clinical oncology 2014 Jul

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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.

Citation

Danielle C Chinn, William S Holland, Philip C Mack. Anticancer activity of the Aurora A kinase inhibitor MK-5108 in non-small-cell lung cancer (NSCLC) in vitro as monotherapy and in combination with chemotherapies. Journal of cancer research and clinical oncology. 2014 Jul;140(7):1137-49