title: MK1775, a selective Wee1 inhibitor, shows single-agent antitumor activity against sarcoma cells.
abstract: Wee1 is a critical component of the G(2)-M cell-cycle checkpoint control and mediates cell-cycle arrest by regulating the phosphorylation of CDC2. Inhibition of Wee1 by a selective small molecule inhibitor MK1775 can abrogate G(2)-M checkpoint, resulting in premature mitotic entry and cell death. MK1775 has recently been tested in preclinical and clinical studies of human carcinoma to enhance the cytotoxic effect of DNA-damaging agents. However, its role in mesenchymal tumors, especially as a single agent, has not been explored. Here, we studied the cytotoxic effect of MK1775 in various sarcoma cell lines and patient-derived tumor explants ex vivo. Our data show that MK1775 treatment at clinically relevant concentrations leads to unscheduled entry into mitosis and initiation of apoptotic cell death in all sarcomas tested. In MK1775-treated cells, CDC2 activity was enhanced, as determined by decreased inhibitory phosphorylation of tyrosine-15 residue and increased expression of phosphorylated histone H3, a marker of mitotic entry. The cytotoxic effect of Wee1 inhibition on sarcoma cells seems to be independent of p53 status as all sarcoma cell lines with different p53 mutation were highly sensitive to MK1775 treatment. Finally, in patient-derived sarcoma samples, we showed that MK1775 as a single agent causes significant apoptotic cell death, suggesting that Wee1 inhibition may represent a novel approach in the treatment of sarcomas.
authors.affiliation: Experimental Therapeutics Program, H Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33612, USA.
authors.forename: Jenny M
authors.initials: JM
authors.lastname: Kreahling
authors.forename: Jennifer Y
authors.initials: JY
authors.lastname: Gemmer
authors.forename: Damon
authors.initials: D
authors.lastname: Reed
authors.forename: Douglas
authors.initials: D
authors.lastname: Letson
authors.forename: Marilyn
authors.initials: M
authors.lastname: Bui
authors.forename: Soner
authors.initials: S
authors.lastname: Altiok
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D016203:CDC2 Protein Kinase; D059447:Cell Cycle Checkpoints / Q000187:drug effects*; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019926:Cyclin B / Q000378:metabolism; D018844:Cyclin-Dependent Kinases; D006657:Histones / Q000378:metabolism; D006801:Humans; D008938:Mitosis / Q000187:drug effects*; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors*; D010766:Phosphorylation / Q000187:drug effects; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011720:Pyrazoles / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D011744:Pyrimidinones; D012509:Sarcoma / Q000473:pathology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D019926:Cyclin B; D006657:Histones; D009687:Nuclear Proteins; D011720:Pyrazoles; D011743:Pyrimidines; D011744:Pyrimidinones; D016159:Tumor Suppressor Protein p53; D011505:Protein-Tyrosine Kinases; C499349:WEE1 protein, human; D016203:CDC2 Protein Kinase; C528899:CDK1 protein, human; D018844:Cyclin-Dependent Kinases; C549567:adavosertib
references.citation: EMBO J. 1997 Feb 3;16(3):545-54
references.pmid: 9034337
references.citation: J Cell Biol. 1996 Aug;134(4):963-70
references.pmid: 8769420
references.citation: Mol Cancer Ther. 2009 Nov;8(11):2992-3000
references.pmid: 19887545
references.citation: Ann Oncol. 2004 Feb;15(2):252-6
references.pmid: 14760118
references.citation: EMBO J. 1993 Jan;12(1):75-85
references.pmid: 8428596
references.citation: Proc Natl Acad Sci U S A. 2007 Apr 24;104(17):7211-6
references.pmid: 17431037
references.citation: Semin Oncol. 1997 Oct;24(5):504-14
references.pmid: 9344316
references.citation: Mol Cancer. 2009 Jun 08;8:34
references.pmid: 19500427
references.citation: PLoS One. 2010 Dec 14;5(12):e14335
references.pmid: 21179472
references.citation: Breast Cancer Res Treat. 2010 Jul;122(2):347-57
references.pmid: 19821025
references.citation: PLoS One. 2010 Apr 08;5(4):e10089
references.pmid: 20386692
references.citation: Cell Div. 2007 May 04;2:12
references.pmid: 17480229
references.citation: Cancer Biol Ther. 2010 Apr 1;9(7):514-22
references.pmid: 20107315
references.citation: J Clin Oncol. 2008 Feb 1;26(4):626-32
references.pmid: 18235122
references.citation: N Engl J Med. 2002 Aug 15;347(7):472-80
references.pmid: 12181401
references.citation: Lancet. 2004 Sep 25-Oct 1;364(9440):1127-34
references.pmid: 15451219
references.citation: Cell Cycle. 2010 Dec 1;9(23):4656-65
references.pmid: 21099353
references.citation: N Engl J Med. 2006 Oct 12;355(15):1572-82
references.pmid: 17035650
references.citation: Genes Dev. 1998 May 15;12(10):1495-503
references.pmid: 9585509
references.citation: Cancer Epidemiol Biomarkers Prev. 2011 Aug;20(8):1770-7
references.pmid: 21724855
references.citation: Adv Enzyme Regul. 1984;22:27-55
references.pmid: 6382953
references.citation: Clin Cancer Res. 2011 Jul 1;17(13):4200-7
references.pmid: 21562035
references.citation: J Clin Oncol. 2000 Jul;18(14):2676-84
references.pmid: 10894866
references.citation: Int J Biol Sci. 2006;2(4):161-70
references.pmid: 16810330
references.citation: Nature. 1991 Sep 5;353(6339):80-3
references.pmid: 1840647
references.citation: CA Cancer J Clin. 2008 Mar-Apr;58(2):71-96
references.pmid: 18287387
references.citation: Curr Biol. 2009 Oct 13;19(19):1670-6
references.pmid: 19800237
references.citation: Chromosoma. 1997 Nov;106(6):348-60
references.pmid: 9362543
references.citation: J Clin Oncol. 2009 May 20;27(15):2536-41
references.pmid: 19349548
references.citation: Genes Chromosomes Cancer. 1992 Jan;4(1):1-15
references.pmid: 1377002
references.citation: Science. 1992 Sep 25;257(5078):1955-7
references.pmid: 1384126
references.citation: Cancer Biol Ther. 2010 Apr 1;9(7):523-5
references.pmid: 20150761
references.citation: Ultrastruct Pathol. 2011 Apr;35(2):66-71
references.pmid: 21299346
references.citation: Clin Cancer Res. 2011 May 1;17(9):2799-806
references.pmid: 21389100