The dual pathway inhibitor rigosertib is effective in direct patient tumor xenografts of head and neck squamous cell carcinomas

Ryan T. Anderson, Stephen B. Keysar, Daniel W. Bowles, Magdalena J. Glogowska, David P. Astling, J. Jason Morton, Phuong Le, Adrian Umpierrez, Justin Eagles-Soukup, Gregory N. Gan, Brian W. Vogler, Daniel Sehrt, Sarah M. Takimoto, Dara L. Aisner, Francois Wilhelm, Barbara A. Frederick, Marileila Varella-Garcia, Aik Choon Tan, Antonio Jimeno

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16 Citations (Scopus)

Abstract

The dual pathway inhibitor rigosertib inhibits phosphoinositide 3-kinase (PI3K) pathway activation as well as polo-like kinase 1 (PLK1) activity across a broad spectrum of cancer cell lines. The importance of PIK3CA alterations in squamous cell carcinoma of the head and neck (HNSCC) has raised interest in exploring agents targeting PI3K, the product of PIK3CA. The genetic and molecular basis of rigosertib treatment response was investigated in a panel of 16 HNSCC cell lines, and direct patient tumor xenografts from eight patients with HNSCC [four HPV-serotype16 (HPV16)-positive]. HNSCC cell lines and xenografts were characterized by pathway enrichment gene expression analysis, exon sequencing, gene copy number, Western blotting, and immunohistochemistry (IHC). Rigosertib had potent antiproliferative effects on 11 of 16 HPV - HNSCC cell lines. Treatment sensitivity was confirmed in two cell lines using an orthotopic in vivo xenograft model. Growth reduction after rigosertib treatment was observed in three of eight HNSCC direct patient tumor lines. The responsive tumor lines carried a combination of a PI3KCAactivating event (amplification or mutation) and a p53-inactivating event (either HPV16- or mutationmediated TP53 inactivation). In this study, we evaluated the in vitro and in vivo efficacy of rigosertib in both HPV + and HPV - HNSCCs, focusing on inhibition of the PI3K pathway. Although consistent inhibition of the PI3K pathway was not evident in HNSCC, we identified a combination of PI3K/TP53 events necessary, but not sufficient, for rigosertib sensitivity.

Original languageEnglish
Pages (from-to)1994-2005
Number of pages12
JournalMolecular cancer therapeutics
Volume12
Issue number10
DOIs
Publication statusPublished - 2013 Oct

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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  • Cite this

    Anderson, R. T., Keysar, S. B., Bowles, D. W., Glogowska, M. J., Astling, D. P., Morton, J. J., Le, P., Umpierrez, A., Eagles-Soukup, J., Gan, G. N., Vogler, B. W., Sehrt, D., Takimoto, S. M., Aisner, D. L., Wilhelm, F., Frederick, B. A., Varella-Garcia, M., Tan, A. C., & Jimeno, A. (2013). The dual pathway inhibitor rigosertib is effective in direct patient tumor xenografts of head and neck squamous cell carcinomas. Molecular cancer therapeutics, 12(10), 1994-2005. https://doi.org/10.1158/1535-7163.MCT-13-0206