title: Activity of the MEK inhibitor selumetinib (AZD6244; ARRY-142886) in nasopharyngeal cancer cell lines.
abstract: This study evaluated the preclinical activity of selumetinib (AZD6244, ARRY-142866), an inhibitor of the mitogen-activated protein kinase kinase (MAPKK or MEK1/2) in 6 nasopharyngeal cancer (NPC) cell lines. Selumetinib could achieve up to 90 % inhibition of cell growth with the respective IC(50) values in NPC cell lines as follow: HK1 = 0.04 μM, HK1-LMP1(B95.8) = 0.17 μM, HONE-1-EBV = 0.46 μM, HONE-1 = 1.79 μM, CNE-2 = 2.20 μM and C666-1 > 10 μM. The drug-sensitive cell lines HK1, HK1-LMP1(B95.8) and HONE-1-EBV have higher basal expression of phosphorylated (pi)-MAPK than the less sensitive cell lines. BRAF mutations were not detected in all 6 cell lines. Re-introduction of the EBV genome into HONE-1 cells, generating the HONE-1-EBV cell line, seemed to result in elevated expression of pi-MAPK and sensitivity to selumetinib when compared with the parental HONE-1 cells. At a concentration of 0.5 μM and 5 μM, selumetinib induced apoptosis (as indicated by cleaved PARP expression and caspase 3 induction), and G(0)/G(1) cycle arrest in HONE-1-EBV and HK1-LMP1(B95.8) cells. The combination of selumetinib (at IC(25) concentration) and the EGFR tyrosine kinase inhibitor, gefitinib (at concentrations of 0.1, 3 and 9 μM) resulted in synergistic growth inhibition in HK1-LMP1(B95.8) cells. The combination of selumetinib (at IC(25) concentration) and cisplatin (at concentrations of 0.1, 0.4, 0.8 and 2 μM) resulted in synergistic growth inhibition in HONE-1 and HONE-1-EBV cells. This result suggests that selumetinib alone or in combination with gefitinib or cisplatin maybe a promising strategy against NPC. Further studies are warranted.
authors.affiliation: State Key Laboratory in Oncology in South China, Sir Y.K. Pao Centre for Cancer, Department of Clinical Oncology, Cancer Drug Testing Unit, Hong Kong Cancer Institute and Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong, China. brigette@clo.cuhk.edu.hk
authors.forename: Brigette B Y
authors.initials: BB
authors.lastname: Ma
authors.forename: Vivian W Y
authors.initials: VW
authors.lastname: Lui
authors.forename: Crystal S
authors.initials: CS
authors.lastname: Cheung
authors.forename: Cecilia P Y
authors.initials: CP
authors.lastname: Lau
authors.forename: Kakiu
authors.initials: K
authors.lastname: Ho
authors.forename: Edwin P
authors.initials: EP
authors.lastname: Hui
authors.forename: Stephen K W
authors.initials: SK
authors.lastname: Tsui
authors.forename: Margaret H
authors.initials: MH
authors.lastname: Ng
authors.forename: S H
authors.initials: SH
authors.lastname: Cheng
authors.forename: Patrick K S
authors.initials: PK
authors.lastname: Ng
authors.forename: Sai Wai
authors.initials: SW
authors.lastname: Tsao
authors.forename: Anthony T C
authors.initials: AT
authors.lastname: Chan
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage*; D017209:Apoptosis / Q000187:drug effects; D001562:Benzimidazoles / Q000008:administration & dosage*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology; D004357:Drug Synergism; D000077156:Gefitinib; D006801:Humans; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009303:Nasopharyngeal Neoplasms / Q000188:drug therapy*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D011799:Quinazolines / Q000494:pharmacology
chemical_list: C517975:AZD 6244; D000970:Antineoplastic Agents; D001562:Benzimidazoles; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D020929:Mitogen-Activated Protein Kinase Kinases; D002945:Cisplatin; D000077156:Gefitinib