title: Mitogen-activated protein kinase (MEK/ERK) inhibition sensitizes cancer cells to centromere-associated protein E inhibition.
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.
authors.affiliation: Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA 19104-4318, USA.
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Mayes
authors.forename: Yan Y
authors.initials: YY
authors.lastname: Degenhardt
authors.forename: Andrew
authors.initials: A
authors.lastname: Wood
authors.forename: Yana
authors.initials: Y
authors.lastname: Toporovskya
authors.forename: Sharon J
authors.initials: SJ
authors.lastname: Diskin
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Haglund
authors.forename: Christopher
authors.initials: C
authors.lastname: Moy
authors.forename: Richard
authors.initials: R
authors.lastname: Wooster
authors.forename: John M
authors.initials: JM
authors.lastname: Maris
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides / Q000494:pharmacology; D014408:Biomarkers, Tumor; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology*; D002166:Camptothecin / Q000031:analogs & derivatives / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002868:Chromosomal Proteins, Non-Histone / Q000037:antagonists & inhibitors*; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000235:genetics; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D006801:Humans; D000077146:Irinotecan; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics; D059566:M Phase Cell Cycle Checkpoints / Q000187:drug effects; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D009447:Neuroblastoma / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000235:genetics; D034622:RNA Interference; D034741:RNA, Small Interfering; D012521:Sarcosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000077204:Temozolomide
chemical_list: C120227:2-(2-chloro-4-iodophenylamino)-N-cyclopropylmethoxy-3,4-difluorobenzamide; D000970:Antineoplastic Agents; D001549:Benzamides; D014408:Biomarkers, Tumor; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002868:Chromosomal Proteins, Non-Histone; C571460:GSK923295; D034741:RNA, Small Interfering; C068688:centromere protein E; D000077146:Irinotecan; D003606:Dacarbazine; D048052:Mitogen-Activated Protein Kinase 3; D002166:Camptothecin; D000077204:Temozolomide; D012521:Sarcosine