title: Preclinical evaluation of the AKT inhibitor MK-2206 in nasopharyngeal carcinoma cell lines.
abstract: Nasopharyngeal carcinoma (NPC) is endemic to Asia and over 40 % of NPC tissues harbor PIK3CA amplifications. This study characterized the preclinical activity of MK-2206, an oral allosteric inhibitor of AKT in 6 NPC cell lines: C666-1, HK1, HONE-1-EBV, HONE-1, CNE-2 and HNE-1. Exposure to increasing concentrations of MK-2206 resulted in over 95 % of growth inhibition in all NPC cell lines with IC50 values in the low micromolar range. Further experiments were performed in 3 representative NPC cell lines: CNE-2 (harbor PIK3CA mutation and most sensitive to MK-2206), C666-1 (carries PIK3CA amplification), and HONE-1-EBV (least sensitive to MK-2206). MK-2206 induced G0/G1 cycle arrest in all 3 cell lines, but could induce apoptosis only in CNE-2 cells. MK-2206 significantly abrogated AKT signaling in all 3 cell lines by inhibiting the activation of AKT and its downstream effectors (FKHR, GSK3β and BAD). MK-2206 also reduced mTOR signaling by reducing activation of mTOR and its downstream 4E-BP1 and p70S6 kinase. MAPK activation was observed in HONE-1 and C666-1 cells, but not in CNE-2 cells following exposure to MK-2206. The addition of MK-2206 to cisplatin (but not with paclitaxel) has a supra-additive inhibitory effect on growth in vitro. In summary, MK-2206 can inhibit growth and abrogate AKT and mTOR signaling in NPC cell lines. This agent is currently being evaluated in a phase II study in metastatic NPC.
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, 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: Connie W C
authors.initials: CW
authors.lastname: Hui
authors.forename: Cecilia P Y
authors.initials: CP
authors.lastname: Lau
authors.forename: Chi-Hang
authors.initials: CH
authors.lastname: Wong
authors.forename: Edwin P
authors.initials: EP
authors.lastname: Hui
authors.forename: Margaret H
authors.initials: MH
authors.lastname: Ng
authors.forename: S W
authors.initials: SW
authors.lastname: Tsao
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.forename: Anthony T C
authors.initials: AT
authors.lastname: Chan
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage*; D002277:Carcinoma; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000008:administration & dosage; D006575:Heterocyclic Compounds, 3-Ring / Q000008:administration & dosage*; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D000077274:Nasopharyngeal Carcinoma; D009303:Nasopharyngeal Neoplasms / Q000378:metabolism*; D017239:Paclitaxel / Q000008:administration & dosage; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D006575:Heterocyclic Compounds, 3-Ring; C548887:MK 2206; D047428:Protein Kinase Inhibitors; C546842:MTOR protein, human; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D020928:Mitogen-Activated Protein Kinases; D017239:Paclitaxel; D002945:Cisplatin