title: Functional genetic screens identify genes essential for tumor cell survival in head and neck and lung cancer.
abstract: OBJECTIVE
  Despite continuous improvement of treatment regimes, the mortality rates for non-small cell lung cancer (NSCLC) and head and neck squamous cell carcinoma (HNSCC) remain disappointingly high and novel anticancer agents are urgently awaited.
  
  
  METHODS
  We combined the data from genome-wide siRNA screens on tumor cell lethality in a lung and a head and neck cancer cell line.
  
  
  RESULTS
  We identified 71 target genes that seem essential for the survival of both cancer types. We identified a cluster of 20 genes that play an important role during G2-M phase transition, underlining the importance of this cell-cycle checkpoint for tumor cell survival. Five genes from this cluster (CKAP5, KPNB1, RAN, TPX2, and KIF11) were evaluated in more detail and have been shown to be essential for tumor cell survival in both tumor types, but most particularly in HNSCC. Phenotypes that were observed following siRNA-mediated knockdown of KIF11 (kinesin family member 11) were reproduced by inhibition of KIF11 using the small-molecule inhibitor ispinesib (SB-715992). We showed that ispinesib induces a G2 arrest, causes aberrant chromosome segregation, and induces cell death in HNSCC in vitro, whereas primary keratinocytes are less sensitive. Furthermore, growth of HNSCC cells engrafted in immunodeficient mice was significantly inhibited after ispinesib treatment.
  
  
  CONCLUSIONS
  This study identified a wide array of druggable genes for both lung and head and neck cancer. In particular, multiple genes involved in the G2-M checkpoint were shown to be essential for tumor cell survival, indicating their potential as anticancer targets.
authors: AuDepartment of Otolaryngology/Head-Neck Surgery, VU University Medical Center, Amsterdam, the Netherlands.
authors: Sanne R
authors: SR
authors: Martens-de Kemp
authors: Remco
authors: R
authors: Nagel
authors: Marijke
authors: M
authors: Stigter-van Walsum
authors: Ida H
authors: IH
authors: van der Meulen
authors: Victor W
authors: VW
authors: van Beusechem
authors: Boudewijn J M
authors: BJ
authors: Braakhuis
authors: Ruud H
authors: RH
authors: Brakenhoff
mesh_terms: D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000473:pathology; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000473:pathology / Q000517:prevention & control; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects / Q000235:genetics; D020043:Genes, Essential / Q000235:genetics; D055106:Genome-Wide Association Study / Q000379:methods; D006258:Head and Neck Neoplasms / Q000235:genetics* / Q000473:pathology / Q000517:prevention & control; D006801:Humans; D016547:Kinesins / Q000235:genetics / Q000378:metabolism; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D028961:beta Karyopherins / Q000235:genetics / Q000378:metabolism; D020931:ran GTP-Binding Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D001549:Benzamides; D018797:Cell Cycle Proteins; C470243:KIF11 protein, human; C424166:KPNB1 protein, human; D008869:Microtubule-Associated Proteins; D009687:Nuclear Proteins; D011799:Quinazolines; C122167:TPX2 protein, human; D028961:beta Karyopherins; C508757:ispinesib; D016547:Kinesins; D020931:ran GTP-Binding Protein