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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.

AbstractPURPOSE:
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.
METHODS:
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.
RESULTS:
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.
CONCLUSIONS:
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.
AuthorsDanielle C Chinn, William S Holland, Philip C Mack
JournalJournal of cancer research and clinical oncology (J Cancer Res Clin Oncol) Vol. 140 Issue 7 Pg. 1137-49 (Jul 2014) ISSN: 1432-1335 [Electronic] Germany
PMID24756365 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • 4-(3-chloro-2-fluorophenoxy)-1-((6-(1,3-thiazol-2-ylamino)pyridin to 2-yl)methyl) cyclohexanecarboxylic acid
  • Cyclohexanecarboxylic Acids
  • Protein Kinase Inhibitors
  • Taxoids
  • Thiazoles
  • Docetaxel
  • Aurora Kinase A
  • Cisplatin
Topics
  • Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
  • Aurora Kinase A (antagonists & inhibitors)
  • Carcinoma, Non-Small-Cell Lung (drug therapy, pathology)
  • Cell Cycle (drug effects)
  • Cell Line, Tumor
  • Cell Proliferation (drug effects)
  • Cisplatin (administration & dosage)
  • Cyclohexanecarboxylic Acids (administration & dosage)
  • Docetaxel
  • Humans
  • Lung Neoplasms (drug therapy, pathology)
  • Protein Kinase Inhibitors (administration & dosage)
  • Taxoids (administration & dosage)
  • Thiazoles (administration & dosage)

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