title: Wee-1 kinase inhibition overcomes cisplatin resistance associated with high-risk TP53 mutations in head and neck cancer through mitotic arrest followed by senescence.
abstract: Although 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.
authors.affiliation: Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Abdullah A
authors.initials: AA
authors.lastname: Osman
authors.affiliation: Department of Surgery, Division of Otolaryngology-Head and Neck Surgery, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, Utah.
authors.forename: Marcus M
authors.initials: MM
authors.lastname: Monroe
authors.affiliation: Department of Internal Medicine, Tufts Medical Center, Boston, Massachusetts.
authors.forename: Marcus V
authors.initials: MV
authors.lastname: Ortega Alves
authors.affiliation: Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Ameeta A
authors.initials: AA
authors.lastname: Patel
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.
authors.forename: Panagiotis
authors.initials: P
authors.lastname: Katsonis
authors.affiliation: Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Alison L
authors.initials: AL
authors.lastname: Fitzgerald
authors.affiliation: Department of Otolaryngology Head and Neck Surgery, Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina.
authors.forename: David M
authors.initials: DM
authors.lastname: Neskey
authors.affiliation: Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Mitchell J
authors.initials: MJ
authors.lastname: Frederick
authors.affiliation: Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Sang Hyeok
authors.initials: SH
authors.lastname: Woo
authors.affiliation: Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Carlos
authors.initials: C
authors.lastname: Caulin
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.
authors.forename: Teng-Kuei
authors.initials: TK
authors.lastname: Hsu
authors.affiliation: Department of Statistics, Rice University, Houston, Texas.
authors.forename: Thomas O
authors.initials: TO
authors.lastname: McDonald
authors.affiliation: Department of Statistics, Rice University, Houston, Texas.
authors.forename: Marek
authors.initials: M
authors.lastname: Kimmel
authors.affiliation: Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Raymond E
authors.initials: RE
authors.lastname: Meyn
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.
authors.forename: Olivier
authors.initials: O
authors.lastname: Lichtarge
authors.affiliation: Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas. jmyers@mdanderson.org.
authors.forename: Jeffrey N
authors.initials: JN
authors.lastname: Myers
mesh_terms: D000818:Animals; D016203:CDC2 Protein Kinase / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000187:drug effects*; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D016922:Cellular Senescence / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004249:DNA Damage; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004357:Drug Synergism; D006258:Head and Neck Neoplasms / Q000235:genetics*; D006801:Humans; D008819:Mice, Nude; D008938:Mitosis / Q000187:drug effects; D009154:Mutation / Q000235:genetics*; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010641:Phenotype; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D011744:Pyrimidinones; D017382:Reactive Oxygen Species / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D009687:Nuclear Proteins; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; D011744:Pyrimidinones; D017382:Reactive Oxygen Species; D016159:Tumor Suppressor Protein p53; D011505:Protein-Tyrosine Kinases; C499349:WEE1 protein, human; D016203:CDC2 Protein Kinase; C549567:adavosertib; D002945:Cisplatin