title: Mutations of the LIM protein AJUBA mediate sensitivity of head and neck squamous cell carcinoma to treatment with cell-cycle inhibitors.
abstract: The genomic alterations identified in head and neck squamous cell carcinoma (HNSCC) tumors have not resulted in any changes in clinical care, making the development of biomarker-driven targeted therapy for HNSCC a major translational gap in knowledge. To fill this gap, we used 59 molecularly characterized HNSCC cell lines and found that mutations of AJUBA, SMAD4 and RAS predicted sensitivity and resistance to treatment with inhibitors of polo-like kinase 1 (PLK1), checkpoint kinases 1 and 2, and WEE1. Inhibition or knockdown of PLK1 led to cell-cycle arrest at the G2/M transition and apoptosis in sensitive cell lines and decreased tumor growth in an orthotopic AJUBA-mutant HNSCC mouse model. AJUBA protein expression was undetectable in most AJUBA-mutant HNSCC cell lines, and total PLK1 and Bora protein expression were decreased. Exogenous expression of wild-type AJUBA in an AJUBA-mutant cell line partially rescued the phenotype of PLK1 inhibitor-induced apoptosis and decreased PLK1 substrate inhibition, suggesting a threshold effect in which higher drug doses are required to affect PLK1 substrate inhibition. PLK1 inhibition was an effective therapy for HNSCC in vitro and in vivo. However, biomarkers to guide such therapy are lacking. We identified AJUBA, SMAD4 and RAS mutations as potential candidate biomarkers of response of HNSCC to treatment with these mitotic inhibitors.
authors.affiliation: Department of Thoracic/Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Otolaryngology-Head & Neck Surgery, Eye Ear Nose and Throat Hospital, Fudan University, Shanghai, People's Republic of China.
authors.forename: Ming
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Department of Thoracic/Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Ratnakar
authors.initials: R
authors.lastname: Singh
authors.affiliation: Department of Thoracic/Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Shaohua
authors.initials: S
authors.lastname: Peng
authors.affiliation: Department of Thoracic/Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Tuhina
authors.initials: T
authors.lastname: Mazumdar
authors.affiliation: Department of Thoracic/Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Vaishnavi
authors.initials: V
authors.lastname: Sambandam
authors.affiliation: Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Shen
authors.affiliation: Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Pan
authors.initials: P
authors.lastname: Tong
authors.affiliation: Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Lerong
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Thoracic/Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Nene N
authors.initials: NN
authors.lastname: Kalu
authors.affiliation: Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; The University of Texas Graduate School of Biomedical Sciences, Houston, TX 77030, USA.
authors.forename: Curtis R
authors.initials: CR
authors.lastname: Pickering
authors.affiliation: Department of Otolaryngology, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Mitchell
authors.initials: M
authors.lastname: Frederick
authors.affiliation: Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; The University of Texas Graduate School of Biomedical Sciences, Houston, TX 77030, USA.
authors.forename: Jeffrey N
authors.initials: JN
authors.lastname: Myers
authors.affiliation: Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; The University of Texas Graduate School of Biomedical Sciences, Houston, TX 77030, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Thoracic/Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; The University of Texas Graduate School of Biomedical Sciences, Houston, TX 77030, USA. Electronic address: fmjohns@mdanderson.org.
authors.forename: Faye M
authors.initials: FM
authors.lastname: Johnson
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D000071877:Checkpoint Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D064447:Checkpoint Kinase 2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D005838:Genotype; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D006801:Humans; D060588:LIM Domain Proteins / Q000235:genetics*; D008819:Mice, Nude; D058990:Molecular Targeted Therapy; D009154:Mutation; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D010641:Phenotype; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011621:Pteridines / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D011744:Pyrimidinones; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects; D051901:Smad4 Protein / Q000235:genetics; D000077195:Squamous Cell Carcinoma of Head and Neck; D013876:Thiophenes / Q000494:pharmacology; D013997:Time Factors; D014162:Transfection; D047368:Tumor Burden / Q000187:drug effects; D014508:Urea / Q000031:analogs & derivatives / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays; D018631:ras Proteins / Q000235:genetics; D000097869:Polo-Like Kinase 1
chemical_list: D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D000071877:Checkpoint Kinase 1; D064447:Checkpoint Kinase 2; D060588:LIM Domain Proteins; D009687:Nuclear Proteins; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D011518:Proto-Oncogene Proteins; D011621:Pteridines; D011720:Pyrazoles; D011743:Pyrimidines; D011744:Pyrimidinones; D051901:Smad4 Protein; D013876:Thiophenes; D014508:Urea; D018631:ras Proteins; D000097869:Polo-Like Kinase 1; C532363:3-(carbamoylamino)-5-(3-fluorophenyl)-N-(3-piperidyl)thiophene-2-carboxamide; C485608:AJUBA protein, human; C541363:BI 6727; C497796:SMAD4 protein, human; C528235:bora protein, human; C499349:WEE1 protein, human; C000605867:CHEK1 protein, human; C578634:CHEK2 protein, human; C549567:adavosertib
keywords: AJUBA; CHK1; Head neck squamous cell carcinoma; Polo-like kinase 1; WEE1