Preclinical evaluation of the AKT inhibitor MK-2206 in nasopharyngeal carcinoma cell lines

Brigette B.Y. Ma, Vivian W.Y. Lui, Connie W.C. Hui, Cecilia P.Y. Lau, Chi Hang Wong, Edwin P. Hui, Margaret H. Ng, S. W. Tsao, Yan Li, Anthony T.C. Chan

Research output: Contribution to journalArticlepeer-review

32 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)567-575
Number of pages9
JournalInvestigational New Drugs
Volume31
Issue number3
DOIs
StatePublished - Jun 2013
Externally publishedYes

Keywords

  • AKT
  • MAPK
  • MK-2206
  • Nasopharyngeal cancer

ASJC Scopus subject areas

  • Oncology
  • Pharmacology
  • Pharmacology (medical)

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