title: Integrated genomic analysis identifies the mitotic checkpoint kinase WEE1 as a novel therapeutic target in medulloblastoma.
abstract: BACKGROUND
  Medulloblastoma is the most common type of malignant brain tumor that afflicts children. Although recent advances in chemotherapy and radiation have improved outcomes, high-risk patients do poorly with significant morbidity.
  
  
  METHODS
  To identify new molecular targets, we performed an integrated genomic analysis using structural and functional methods. Gene expression profiling in 16 medulloblastoma patient samples and subsequent gene set enrichment analysis indicated that cell cycle-related kinases were associated with disease development. In addition a kinome-wide small interfering RNA (siRNA) screen was performed to identify kinases that, when inhibited, could prevent cell proliferation. The two genome-scale analyses were combined to identify key vulnerabilities in medulloblastoma. The inhibition of one of the identified targets was further investigated using RNAi and a small molecule inhibitor.
  
  
  RESULTS
  Combining the two analyses revealed that mitosis-related kinases were critical determinants of medulloblastoma cell proliferation. RNA interference (RNAi)-mediated knockdown of WEE1 kinase and other mitotic kinases was sufficient to reduce medulloblastoma cell proliferation. These data prompted us to examine the effects of inhibiting WEE1 by RNAi and by a small molecule inhibitor of WEE1, MK-1775, in medulloblastoma cell lines. MK-1775 inhibited the growth of medulloblastoma cell lines, induced apoptosis and increased DNA damage at nanomolar concentrations. Further, MK-1775 was synergistic with cisplatin in reducing medulloblastoma cell proliferation and resulted in an associated increase in cell death. In vivo MK-1775 suppressed medulloblastoma tumor growth as a single agent.
  
  
  CONCLUSIONS
  Taken together, these findings highlight mitotic kinases and, in particular, WEE1 as a rational therapeutic target for medulloblastoma.
authors.forename: Peter S
authors.initials: PS
authors.lastname: Harris
authors.forename: Sujatha
authors.initials: S
authors.lastname: Venkataraman
authors.forename: Irina
authors.initials: I
authors.lastname: Alimova
authors.forename: Diane K
authors.initials: DK
authors.lastname: Birks
authors.forename: Ilango
authors.initials: I
authors.lastname: Balakrishnan
authors.forename: Brian
authors.initials: B
authors.lastname: Cristiano
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Donson
authors.forename: Adrian M
authors.initials: AM
authors.lastname: Dubuc
authors.forename: Michael D
authors.initials: MD
authors.lastname: Taylor
authors.forename: Nicholas K
authors.initials: NK
authors.lastname: Foreman
authors.forename: Philip
authors.initials: P
authors.lastname: Reigan
authors.affiliation: Department of Pediatrics and Section of Pediatric Hematology/Oncology/BMT, Children's Hospital Colorado and University of Colorado Denver, Anschutz Medical Campus, 12800 E 19th Ave, Mail Stop 8302, Aurora, CO, 80045, USA. rajeev.vibhakar@ucdenver.edu.
authors.forename: Rajeev
authors.initials: R
authors.lastname: Vibhakar
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000235:genetics; D018797:Cell Cycle Proteins / Q000096:biosynthesis* / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002675:Child, Preschool; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D015894:Genome, Human; D023281:Genomics; D006801:Humans; D008527:Medulloblastoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D058990:Molecular Targeted Therapy; D009687:Nuclear Proteins / Q000096:biosynthesis* / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage; D011505:Protein-Tyrosine Kinases / Q000096:biosynthesis* / Q000235:genetics; D011720:Pyrazoles / Q000008:administration & dosage; D011743:Pyrimidines / Q000008:administration & dosage; D011744:Pyrimidinones
chemical_list: D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; D011744:Pyrimidinones; D011505:Protein-Tyrosine Kinases; C499349:WEE1 protein, human; C549567:adavosertib