Functional kinomics identifies candidate therapeutic targets in head and neck cancer

Russell Moser, Chang Xu, Michael Kao, James Annis, Luisa Angelica Lerma, Christopher M. Schaupp, Kay E. Gurley, In Sock Jang, Asel Biktasova, Wendell G. Yarbrough, Adam Margolin, Carla Grandori, Christopher J. Kemp, Eduardo Méndez

Research output: Contribution to journalArticle

40 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)4274-4288
Number of pages15
JournalClinical Cancer Research
Volume20
Issue number16
DOIs
Publication statusPublished - Aug 15 2014
Externally publishedYes

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ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Moser, R., Xu, C., Kao, M., Annis, J., Lerma, L. A., Schaupp, C. M., ... Méndez, E. (2014). Functional kinomics identifies candidate therapeutic targets in head and neck cancer. Clinical Cancer Research, 20(16), 4274-4288. https://doi.org/10.1158/1078-0432.CCR-13-2858