title: Chk1/2 inhibition overcomes the cisplatin resistance of head and neck cancer cells secondary to the loss of functional p53.
abstract: Despite the use of multimodality therapy using cisplatin to treat patients with advanced stage squamous cell carcinoma of the head and neck (HNSCC), there is an unacceptably high rate of treatment failure. TP53 is the most commonly mutated gene in HNSCC, and the impact of p53 mutation on response to cisplatin treatment is poorly understood. Here, we show unambiguously that wild-type TP53 (wtp53) is associated with sensitivity of HNSCC cells to cisplatin treatment, whereas mutation or loss of TP53 is associated with cisplatin resistance. We also show that senescence is the major cellular response to cisplatin in wtp53 HNSCC cells and that cisplatin resistance in p53-null or -mutant TP53 cells is due to their lack of senescence. Given the dependence on checkpoint kinase (Chk)1/2 kinases to mediate the DNA damage response in p53-deficient cells, there is potential to exploit this to therapeutic advantage through targeted inhibition of the Chk1/2 kinases. Treatment of p53-deficient HNSCC cells with the Chk inhibitor AZD7762 sensitizes them to cisplatin through induction of mitotic cell death. This is the first report showing the ability of a Chk kinase inhibitor to sensitize TP53-deficient HNSCC to cisplatin in a synthetic lethal manner, which has significance given the frequency of TP53 mutations in this disease and because cisplatin has become part of standard therapy for aggressive HNSCC tumors. These preclinical data provide evidence that a personalized approach to the treatment of HNSCC based on Chk inhibition in p53-mutant tumors may be feasible.
authors.affiliation: Corresponding Authors: Mitchell J. Frederick, Department of Head & Neck Surgery, University of Texas, MD Anderson Cancer Center, 1515 Holcombe Blvd., Unit 1445, Houston, TX 77030. mfrederi@mdanderson.org.
authors.forename: Mayur A
authors.initials: MA
authors.lastname: Gadhikar
authors.forename: Maria Rita
authors.initials: MR
authors.lastname: Sciuto
authors.forename: Marcus Vinicius Ortega
authors.initials: MV
authors.lastname: Alves
authors.forename: Curtis R
authors.initials: CR
authors.lastname: Pickering
authors.forename: Abdullah A
authors.initials: AA
authors.lastname: Osman
authors.forename: David M
authors.initials: DM
authors.lastname: Neskey
authors.forename: Mei
authors.initials: M
authors.lastname: Zhao
authors.forename: Alison L
authors.initials: AL
authors.lastname: Fitzgerald
authors.forename: Jeffrey N
authors.initials: JN
authors.lastname: Myers
authors.forename: Mitchell J
authors.initials: MJ
authors.lastname: Frederick
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D016922:Cellular Senescence / Q000187:drug effects; D000071877:Checkpoint Kinase 1; D064447:Checkpoint Kinase 2 / Q000378:metabolism*; D002945:Cisplatin / Q000494:pharmacology* / Q000627:therapeutic use; D004249:DNA Damage; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D006258:Head and Neck Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D008938:Mitosis; D058990:Molecular Targeted Therapy; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D011494:Protein Kinases / Q000378:metabolism*; D015398:Signal Transduction; D013876:Thiophenes / Q000494:pharmacology* / Q000627:therapeutic use; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism; D014508:Urea / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: C532363:3-(carbamoylamino)-5-(3-fluorophenyl)-N-(3-piperidyl)thiophene-2-carboxamide; D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; C495901:TP53 protein, human; D013876:Thiophenes; D016159:Tumor Suppressor Protein p53; D014508:Urea; D011494:Protein Kinases; D064447:Checkpoint Kinase 2; C000605867:CHEK1 protein, human; C578634:CHEK2 protein, human; D000071877:Checkpoint Kinase 1; D002945:Cisplatin