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Clin Cancer Res. 2014 Aug 15;20(16):4274-88. doi: 10.1158/1078-0432.CCR-13-2858.

Functional kinomics identifies candidate therapeutic targets in head and neck cancer.

Author information

  • 1Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington.
  • 2Department of Otolaryngology: Head and Neck Surgery, University of Washington Medical Center, Seattle, Washington. Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, Washington.
  • 3Department of Otolaryngology: Head and Neck Surgery, University of Washington Medical Center, Seattle, Washington.
  • 4Quellos High Throughput Facility, Institute for Stem Cell And Regenerative Medicine, University of Washington Medicine Research, Seattle, Washington.
  • 5Toxicology Program, Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, Washington.
  • 6Sage Bionetworks, Seattle, Washington.
  • 7Deparment of Surgery, Otolaryngology: Head and Neck Surgery, Yale University School of Medicine, New Haven, Connecticut.
  • 8Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington. Quellos High Throughput Facility, Institute for Stem Cell And Regenerative Medicine, University of Washington Medicine Research, Seattle, Washington.
  • 9Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington. edmendez@u.washington.edu cjkemp@fhcrc.org.
  • 10Department of Otolaryngology: Head and Neck Surgery, University of Washington Medical Center, Seattle, Washington. Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, Washington. Surgery and Perioperative Care Service, VA Puget Sound Health Care System, Seattle, Washington. edmendez@u.washington.edu cjkemp@fhcrc.org.

Abstract

PURPOSE:

To identify novel therapeutic drug targets for p53-mutant head and neck squamous cell carcinoma (HNSCC).

EXPERIMENTAL DESIGN:

RNAi kinome viability screens were performed on HNSCC cells, including autologous pairs from primary tumor and recurrent/metastatic lesions, and in parallel on murine squamous cell carcinoma (MSCC) cells derived from tumors of inbred mice bearing germline mutations in Trp53, and p53 regulatory genes: Atm, Prkdc, and p19(Arf). Cross-species analysis of cell lines stratified by p53 mutational status and metastatic phenotype was used to select 38 kinase targets. Both primary and secondary RNAi validation assays were performed on additional HNSCC cell lines to credential these kinase targets using multiple phenotypic endpoints. Kinase targets were also examined via chemical inhibition using a panel of kinase inhibitors. A preclinical study was conducted on the WEE1 kinase inhibitor, MK-1775.

RESULTS:

Our functional kinomics approach identified novel survival kinases in HNSCC involved in G2-M cell-cycle checkpoint, SFK, PI3K, and FAK pathways. RNAi-mediated knockdown and chemical inhibition of the WEE1 kinase with a specific inhibitor, MK-1775, had a significant effect on both viability and apoptosis. Sensitivity to the MK-1775 kinase inhibitor is in part determined by p53 mutational status, and due to unscheduled mitotic entry. MK-1775 displays single-agent activity and potentiates the efficacy of cisplatin in a p53-mutant HNSCC xenograft model.

CONCLUSIONS:

WEE1 kinase is a potential therapeutic drug target for HNSCC. This study supports the application of a functional kinomics strategy to identify novel therapeutic targets for cancer.

©2014 American Association for Cancer Research.

PMID:
25125259
[PubMed - in process]
PMCID:
PMC4135446
[Available on 2015-08-15]
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