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

TitlePreclinical evaluation of the AKT inhibitor MK-2206 in nasopharyngeal carcinoma cell lines
Authors
Issue Date2013
Citation
Investigational New Drugs, 2013, v. 31 n. 3, p. 567-575 How to Cite?
AbstractNasopharyngeal 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. © 2012 Springer Science+Business Media New York.
Persistent Identifierhttp://hdl.handle.net/10722/194399
ISSN
2015 Impact Factor: 3.281
2015 SCImago Journal Rankings: 1.376
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorMa, BBY-
dc.contributor.authorLui, VWY-
dc.contributor.authorHui, CWC-
dc.contributor.authorLau, CPY-
dc.contributor.authorWong, C-H-
dc.contributor.authorHui, EP-
dc.contributor.authorNg, MH-
dc.contributor.authorTsao, SW-
dc.contributor.authorLi, Y-
dc.contributor.authorChan, ATC-
dc.date.accessioned2014-01-30T03:32:32Z-
dc.date.available2014-01-30T03:32:32Z-
dc.date.issued2013-
dc.identifier.citationInvestigational New Drugs, 2013, v. 31 n. 3, p. 567-575-
dc.identifier.issn0167-6997-
dc.identifier.urihttp://hdl.handle.net/10722/194399-
dc.description.abstractNasopharyngeal 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. © 2012 Springer Science+Business Media New York.-
dc.languageeng-
dc.relation.ispartofInvestigational New Drugs-
dc.titlePreclinical evaluation of the AKT inhibitor MK-2206 in nasopharyngeal carcinoma cell lines-
dc.typeArticle-
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1007/s10637-012-9896-5-
dc.identifier.pmid23143779-
dc.identifier.scopuseid_2-s2.0-84879106545-
dc.identifier.hkuros217817-
dc.identifier.volume31-
dc.identifier.issue3-
dc.identifier.spage567-
dc.identifier.epage575-
dc.identifier.isiWOS:000318657000008-

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