Mitogen-activated protein kinase (MEK/ERK) inhibition sensitizes cancer cells to centromere-associated protein E inhibition

Authors

  • Patrick A. Mayes,

    1. Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA
    2. Department of Pediatrics, Perlman School of Medicine at the University of Pennsylvania, Philadelphia, PA
    Current affiliation:
    1. GlaxoSmithKline, Cancer Research, Collegeville, PA, USA
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  • Yan Y. Degenhardt,

    1. Cancer Research, GlaxoSmithKline, Collegeville, PA
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  • Andrew Wood,

    1. Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA
    2. Department of Pediatrics, Perlman School of Medicine at the University of Pennsylvania, Philadelphia, PA
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  • Yana Toporovskya,

    1. Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA
    2. Department of Pediatrics, Perlman School of Medicine at the University of Pennsylvania, Philadelphia, PA
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  • Sharon J. Diskin,

    1. Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA
    2. Department of Pediatrics, Perlman School of Medicine at the University of Pennsylvania, Philadelphia, PA
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  • Elizabeth Haglund,

    1. Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA
    2. Department of Pediatrics, Perlman School of Medicine at the University of Pennsylvania, Philadelphia, PA
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  • Christopher Moy,

    1. Cancer Research, GlaxoSmithKline, Collegeville, PA
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  • Richard Wooster,

    1. Cancer Research, GlaxoSmithKline, Collegeville, PA
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  • John M. Maris

    Corresponding author
    1. Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA
    2. Department of Pediatrics, Perlman School of Medicine at the University of Pennsylvania, Philadelphia, PA
    3. Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, Philadelphia, PA
    • Children's Hospital of Philadelphia, CTRB 3060, 3501 Civic Center Boulevard, Philadelphia, PA 19104-4318, USA
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    • Tel.: [+215-590-5244], Fax: [+267-426-0685]


Abstract

Inhibition of centromere-associated protein-E (CENP-E) has demonstrated preclinical anti-tumor activity in a number of tumor types including neuroblastoma. A potent small molecule inhibitor of the kinesin motor activity of CENP-E has recently been developed (GSK923295). To identify an effective drug combination strategy for GSK923295 in neuroblastoma, we performed a screen of siRNAs targeting a prioritized set of genes that function in therapeutically tractable signaling pathways. We found that siRNAs targeted to extracellular signal-related kinase 1 (ERK1) significantly sensitized neuroblastoma cells to GSK923295-induced growth inhibition (p = 0.01). Inhibition of ERK1 activity using pharmacologic inhibitors of mitogen-activated ERK kinase (MEK1/2) showed significant synergistic growth inhibitory activity when combined with GSK923295 in neuroblastoma, lung, pancreatic and colon carcinoma cell lines. Synergistic growth inhibitory activity of combined MEK/ERK and CENP-E inhibition was a result of increased mitotic arrest and apoptosis. There was a significant correlation between ERK1/2 phosphorylation status in neuroblastoma cell lines and GSK923295 growth inhibitory activity (r = 0.823, p = 0.0006). Consistent with this result we found that lung cancer cell lines harboring RAS mutations, which leads to oncogenic activation of MEK/ERK signaling, were significantly more resistant than cell lines with wild-type RAS to GSK923295-induced growth inhibition (p = 0.047). Here we have identified (MEK/ERK) activity as a potential biomarker of relative GSK923295 sensitivity and have shown the synergistic effect of combinatorial MEK/ERK pathway and CENP-E inhibition across different cancer cell types including neuroblastoma.

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