Mitogen‐activated protein kinase (MEK/ERK) inhibition sensitizes cancer cells to centromere‐associated protein E inhibition. Issue 3 (28th September 2012)

• Record Type: Journal Article
• Authors: Mayes, Patrick A.; Degenhardt, Yan Y.; Wood, Andrew; Toporovskya, Yana; Diskin, Sharon J.; Haglund, Elizabeth; Moy, Christopher; Wooster, Richard; Maris, John M.
• Is Part Of: International journal of cancer. Volume 132:Issue 3(2013:Feb. 01)
• Page Start: E149
• Page End: E157
• Publication Date: 2012-09-28
• Subjects: Cancer -- Periodicals; Cancer -- Prevention -- Periodicals; 616.994
• DOI: 10.1002/ijc.27781
• Languages: English
• ISSNs: 0020-7136

Abstract

<abstract abstract-type="main" xml:lang="en"> <title>Abstract</title> <p>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 (<italic>p</italic> = 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 (<italic>r</italic> = 0.823, <italic>p</italic> = 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 (<italic>p</italic> = 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.</p> </abstract>