Wee-1 Kinase Inhibition Overcomes Cisplatin Resistance Associated with High-RiskTP53ﾠMutations in Head and Neck Cancer through Mitotic Arrest Followed by Senescence

Simple item page
dc.citation.firstpage608en_US
dc.citation.issueNumber2en_US
dc.citation.journalTitleMolecular Cancer Therapeuticsen_US
dc.citation.lastpage619en_US
dc.citation.volumeNumber14en_US
dc.contributor.authorOsman, Abdullah A.en_US
dc.contributor.authorMonroe, Marcus M.en_US
dc.contributor.authorAlves, Marcus V. Ortegaen_US
dc.contributor.authorPatel, Ameeta A.en_US
dc.contributor.authorKatsonis, Panagiotisen_US
dc.contributor.authorFitzgerald, Alison L.en_US
dc.contributor.authorNeskey, David M.en_US
dc.contributor.authorFrederick, Mitchell J.en_US
dc.contributor.authorWoo, Sang Hyeoken_US
dc.contributor.authorCaulin, Carlosen_US
dc.contributor.authorHsu, Teng-Kueien_US
dc.contributor.authorMcDonald, Thomas O.en_US
dc.contributor.authorKimmel, Mareken_US
dc.contributor.authorMeyn, Raymond E.en_US
dc.contributor.authorLichtarge, Olivieren_US
dc.contributor.authorMyers, Jeffrey N.en_US
dc.date.accessioned2016-06-22T20:08:01Zen_US
dc.date.available2016-06-22T20:08:01Zen_US
dc.date.issued2015en_US
dc.description.abstractAlthough cisplatin has played a role in "standard-of-care" multimodality therapy for patients with advanced squamous cell carcinoma of the head and neck (HNSCC), the rate of treatment failure remains particularly high for patients receiving cisplatin whose tumors have mutations in the TP53 gene. We found that cisplatin treatment of HNSCC cells with mutant TP53 leads to arrest of cells in the G2 phase of the cell cycle, leading us to hypothesize that the wee-1 kinase inhibitor MK-1775 would abrogate the cisplatin-induced G2 block and thereby sensitize isogenic HNSCC cells with mutant TP53 or lacking p53 expression to cisplatin. We tested this hypothesis using clonogenic survival assays, flow cytometry, and in vivo tumor growth delay experiments with an orthotopic nude mouse model of oral tongue cancer. We also used a novel TP53 mutation classification scheme to identify which TP53 mutations are associated with limited tumor responses to cisplatin treatment. Clonogenic survival analyses indicate that nanomolar concentration of MK-1775 sensitizes HNSCC cells with high-risk mutant p53 to cisplatin. Consistent with its ability to chemosensitize, MK-1775 abrogated the cisplatin-induced G2 block in p53-defective cells leading to mitotic arrest associated with a senescence-like phenotype. Furthermore, MK-1775 enhanced the efficacy of cisplatin in vivo in tumors harboring TP53 mutations. These results indicate that HNSCC cells expressing high-risk p53 mutations are significantly sensitized to cisplatin therapy by the selective wee-1 kinase inhibitor, supporting the clinical evaluation of MK-1775 in combination with cisplatin for the treatment of patients with TP53 mutant HNSCC.en_US
dc.identifier.citationOsman, Abdullah A., Monroe, Marcus M., Alves, Marcus V. Ortega, et al.. "Wee-1 Kinase Inhibition Overcomes Cisplatin Resistance Associated with High-RiskTP53ﾠMutations in Head and Neck Cancer through Mitotic Arrest Followed by Senescence." <i>Molecular Cancer Therapeutics,</i> 14, no. 2 (2015) American Association for Cancer Research: 608-619. http://dx.doi.org/10.1158/1535-7163.MCT-14-0735-T.en_US
dc.identifier.doihttp://dx.doi.org/10.1158/1535-7163.MCT-14-0735-Ten_US
dc.identifier.urihttps://hdl.handle.net/1911/90533en_US
dc.language.isoengen_US
dc.publisherAmerican Association for Cancer Researchen_US
dc.rightsThis is an author's peer-reviewed final manuscript, as accepted by the publisher. The published article is copyrighted by the American Association for Cancer Research.en_US
dc.titleWee-1 Kinase Inhibition Overcomes Cisplatin Resistance Associated with High-RiskTP53ﾠMutations in Head and Neck Cancer through Mitotic Arrest Followed by Senescenceen_US
dc.typeJournal articleen_US
dc.type.dcmiTexten_US
dc.type.publicationpost-printen_US
Files
Original bundle
Now showing 1 - 1 of 1
Thumbnail Image
Name:
nihms692472.pdf
Size:
1.94 MB
Format:
Adobe Portable Document Format
Description:
Download
Collections
Faculty Publications
Statistics Publications