title: 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.
abstract: OBJECTIVE
  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.
authors.affiliation: Division of Hematology/Oncology, UC Davis Cancer Center, 4501 X Street, Suite 3016, Sacramento, CA, 95817, USA.
authors.forename: Danielle C
authors.initials: DC
authors.lastname: Chinn
authors.forename: William S
authors.initials: WS
authors.lastname: Holland
authors.forename: Philip C
authors.initials: PC
authors.lastname: Mack
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D064096:Aurora Kinase A / Q000037:antagonists & inhibitors*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000008:administration & dosage; D003509:Cyclohexanecarboxylic Acids / Q000008:administration & dosage*; D000077143:Docetaxel; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage*; D043823:Taxoids / Q000008:administration & dosage; D013844:Thiazoles / Q000008:administration & dosage*
chemical_list: C547876:4-(3-chloro-2-fluorophenoxy)-1-((6-(1,3-thiazol-2-ylamino)pyridin to 2-yl)methyl) cyclohexanecarboxylic acid; D003509:Cyclohexanecarboxylic Acids; D047428:Protein Kinase Inhibitors; D043823:Taxoids; D013844:Thiazoles; D000077143:Docetaxel; D064096:Aurora Kinase A; D002945:Cisplatin
references.citation: Oncogene. 2005 Nov 10;24(49):7266-72
references.pmid: 16027732
references.citation: EMBO Rep. 2010 Dec;11(12):977-84
references.pmid: 21072059
references.citation: Expert Opin Drug Discov. 2011 Mar;6(3):291-307
references.pmid: 21556291
references.citation: Clin Cancer Res. 2008 Mar 15;14(6):1639-48
references.pmid: 18347165
references.citation: Head Neck. 2009 May;31(5):625-34
references.pmid: 19107951
references.citation: J Med Chem. 2009 May 14;52(9):2629-51
references.pmid: 19320489
references.citation: Clin Lung Cancer. 2006 May;7(6):385-8
references.pmid: 16800963
references.citation: Adv Enzyme Regul. 1984;22:27-55
references.pmid: 6382953
references.citation: Cell Cycle. 2007 Jan 1;6(1):70-4
references.pmid: 17245109
references.citation: Anticancer Drugs. 2010 Apr;21(4):339-50
references.pmid: 20016367
references.citation: Invest New Drugs. 2016 Feb;34(1):84-95
references.pmid: 26620496
references.citation: Oncogene. 1997 Feb 6;14(5):543-9
references.pmid: 9053852
references.citation: Bioorg Med Chem Lett. 2009 Jul 1;19(13):3586-92
references.pmid: 19447622
references.citation: Proc Natl Acad Sci U S A. 2007 Mar 6;104(10):4106-11
references.pmid: 17360485
references.citation: Mol Cell Biol. 2006 Dec;26(24):9377-86
references.pmid: 17000754
references.citation: Cancer Res. 2011 Jun 1;71(11):3912-20
references.pmid: 21502403
references.citation: Mol Cancer Ther. 2010 Jan;9(1):157-66
references.pmid: 20053775
references.citation: Carcinogenesis. 2007 Feb;28(2):350-5
references.pmid: 16926177
references.citation: Clin Cancer Res. 2012 Jun 15;18(12):3352-65
references.pmid: 22535157
references.citation: Cell Cycle. 2012 Feb 15;11(4):807-17
references.pmid: 22293494
references.citation: J Transl Med. 2011 Jun 30;9:100
references.pmid: 21718475
references.citation: Clin Cancer Res. 2006 Dec 1;12(23):6869-75
references.pmid: 17145803
references.citation: Nature. 2008 Sep 4;455(7209):119-23
references.pmid: 18615013
references.citation: Pathol Int. 2006 Sep;56(9):503-9
references.pmid: 16930330
references.citation: Mol Cancer Ther. 2012 Mar;11(3):710-9
references.pmid: 22222631
references.citation: Int J Cancer. 2014 Aug 1;135(3):751-62
references.pmid: 24382688
references.citation: J Cell Sci. 2007 Sep 1;120(Pt 17):2987-96
references.pmid: 17715155
references.citation: Invest New Drugs. 2012 Apr;30(2):425-34
references.pmid: 20960027
references.citation: Pediatr Blood Cancer. 2012 Jun;58(6):885-90
references.pmid: 21796766
references.citation: Proc Natl Acad Sci U S A. 2002 Nov 26;99(24):15440-5
references.pmid: 12422018
references.citation: Cancer Res. 2005 Apr 1;65(7):2899-905
references.pmid: 15805292
references.citation: Oncogene. 2012 Jan 12;31(2):135-48
references.pmid: 21685933
references.citation: Genes Cells. 2002 Jan;7(1):11-7
references.pmid: 11856369
references.citation: Cancer Res. 2007 Jun 1;67(11):5362-70
references.pmid: 17545617
references.citation: Leuk Lymphoma. 2012 Mar;53(3):462-71
references.pmid: 21879811
references.citation: Proc Natl Acad Sci U S A. 2004 Jun 8;101(23):8625-30
references.pmid: 15173575
references.citation: Cell Div. 2009 Jan 22;4:4
references.pmid: 19161615
references.citation: Blood. 2010 Jun 24;115(25):5202-13
references.pmid: 20382844
references.citation: Nat Rev Cancer. 2005 Jan;5(1):42-50
references.pmid: 15630414
references.citation: Clin Cancer Res. 2007 Feb 15;13(4):1331-40
references.pmid: 17317845