Integrated genomic analysis identifies the mitotic checkpoint kinase WEE1 as a novel therapeutic target in medulloblastoma

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• 作者：Peter S Harris (9)
  Sujatha Venkataraman (9)
  Irina Alimova (9)
  Diane K Birks (10)
  Ilango Balakrishnan (9)
  Brian Cristiano (9)
  Andrew M Donson (9)
  Adrian M Dubuc (12)
  Michael D Taylor (12)
  Nicholas K Foreman (9)
  Philip Reigan (11)
  Rajeev Vibhakar (9)
  
• 关键词：Medulloblastoma ; WEE1 ; Mitosis ; MK ; 1775 ; Integrated genomics
• 刊名：Molecular Cancer
• 出版年：2014
• 出版时间：December 2014
• 年：2014
• 卷：13
• 期：1
• 全文大小：1,507 KB
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• 作者单位：Peter S Harris (9)
  Sujatha Venkataraman (9)
  Irina Alimova (9)
  Diane K Birks (10)
  Ilango Balakrishnan (9)
  Brian Cristiano (9)
  Andrew M Donson (9)
  Adrian M Dubuc (12)
  Michael D Taylor (12)
  Nicholas K Foreman (9)
  Philip Reigan (11)
  Rajeev Vibhakar (9)
  
  9. Department of Pediatrics and Section of Pediatric Hematology/Oncology/BMT, Children鈥檚 Hospital Colorado and University of Colorado Denver, Anschutz Medical Campus, 12800 E 19th Ave, Mail Stop 8302, Aurora, CO, 80045, USA
  10. Department of Neurosurgery, Children鈥檚 Hospital Colorado and University of Colorado Denver, Anschutz Medical Campus, 12800 E 19th Ave, Mail Stop 8302, Aurora, CO, 80045, USA
  12. Division of Neurosurgery, Arthur & Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, 555 University Ave, Rm 1503, Toronto, ON, M5G 1X8, Canada
  11. Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Denver, Anschutz Medical Campus, 12850 E Montview Blvd, Mail Stop C238, Aurora, CO, 80045, USA
  
• ISSN：1476-4598

文摘

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.