MK-2206 causes growth suppression and reduces neuroendocrine tumor marker production in medullary thyroid cancer through Akt inhibition. Ann Surg Oncol 2013 Nov;20(12):3862-8
Date
08/01/2013Pubmed ID
23900743Pubmed Central ID
PMC3955957DOI
10.1245/s10434-013-3168-2Scopus ID
2-s2.0-84886092179 (requires institutional sign-in at Scopus site) 11 CitationsAbstract
BACKGROUND: Development of targeted therapies for medullary thyroid cancer (MTC) has focused on inhibition of the rearranged during transfection (RET) proto-oncogene. Akt has been demonstrated to be a downstream target of RET via the key mediator phosphoinositide-3-kinase. MK-2206 is an orally administered allosteric Akt inhibitor that has exhibited minimal toxicity in phase I trials. We explored the antitumor effects of this compound in MTC.
METHODS: Human MTC-TT cells were treated with MK-2206 (0-20 μM) for 8 days. Assays for cell viability were performed at multiple time points with MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide). The mechanism of action, mechanism of growth inhibition, and production of neuroendocrine tumor markers were assessed with Western blot analysis.
RESULTS: MK-2206 suppressed MTC cell proliferation in a dose-dependent manner (p ≤ 0.001). Levels of Akt phosphorylated at serine 473 declined with increasing doses of MK-2206, indicating successful Akt inhibition. The apoptotic proteins cleaved poly (ADP-ribose) polymerase and cleaved caspase-3 increased in a dose-dependent manner with MK-2206, while the apoptosis inhibitor survivin was markedly reduced. Importantly, the antitumor effects of MK-2206 were independent of RET inhibition, as the levels of RET protein were not blocked.
CONCLUSIONS: MK-2206 significantly suppresses MTC proliferation without RET inhibition. Given its high oral bioavailability and low toxicity profile, phase II studies with this drug alone or in combination with RET inhibitors are warranted.
Author List
Burke JF, Schlosser L, Harrison AD, Kunnimalaiyaan M, Chen HMESH terms used to index this publication - Major topics in bold
ApoptosisBasic Helix-Loop-Helix Transcription Factors
Biomarkers, Tumor
Blotting, Western
Carcinoma, Medullary
Caspase 3
Cell Proliferation
Chromogranin A
Heterocyclic Compounds, 3-Ring
Humans
Neuroendocrine Tumors
Phosphorylation
Poly(ADP-ribose) Polymerases
Proto-Oncogene Proteins c-akt
Thyroid Neoplasms
Tumor Cells, Cultured
