Antitumor effects of the investigational selective MEK inhibitor TAK733 against cutaneous and uveal melanoma cell lines

Mol Cancer. 2012 Apr 19;11:22. doi: 10.1186/1476-4598-11-22.

Abstract

Background: TAK733 is a novel allosteric, non-ATP-binding, inhibitor of the BRAF substrates MEK-1/2.

Methods: The growth inhibitory effects of TAK733 were assessed in a panel of 27 cutaneous and five uveal melanoma cell lines genotyped for driver oncogenic mutations. Flow cytometry, Western blots and metabolic tracer uptake assays were used to characterize the changes induced by exposure to TAK733.

Results: Fourteen cutaneous melanoma cell lines with different driver mutations were sensitive to the antiproliferative effects of TAK733, with a higher proportion of BRAFV600E mutant cell lines being highly sensitive with IC50s below 1 nM. The five uveal melanoma cell lines had GNAQ or GNA11 mutations and were either moderately or highly sensitive to TAK733. The tested cell lines wild type for NRAS, BRAF, GNAQ and GNA11 driver mutations were moderately to highly resistant to TAK733. TAK733 led to a decrease in pERK and G1 arrest in most of these melanoma cell lines regardless of their origin, driver oncogenic mutations and in vitro sensitivity to TAK733. MEK inhibition resulted in increase in pMEK more prominently in NRASQ61L mutant and GNAQ mutant cell lines than in BRAFV600E mutant cell lines. Uptake of the metabolic tracers FDG and FLT was inhibited by TAK733 in a manner that closely paralleled the in vitro sensitivity assays.

Conclusions: The MEK inhibitor TAK733 has antitumor properties in melanoma cell lines with different oncogenic mutations and these effects could be detectable by differential metabolic tracer uptake.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Cell Cycle / drug effects
  • Cell Line, Tumor
  • Drug Resistance, Neoplasm
  • Humans
  • Inhibitory Concentration 50
  • MAP Kinase Signaling System / drug effects*
  • Melanoma / metabolism*
  • Phosphatidylinositol 3-Kinases / metabolism
  • Protein Kinase Inhibitors / pharmacology*
  • Proto-Oncogene Proteins c-akt / metabolism
  • Pyridones / pharmacology*
  • Pyrimidinones / pharmacology*
  • Radioactive Tracers
  • Signal Transduction / drug effects
  • Skin Neoplasms / metabolism*
  • Uveal Neoplasms / metabolism*

Substances

  • Antineoplastic Agents
  • Protein Kinase Inhibitors
  • Pyridones
  • Pyrimidinones
  • Radioactive Tracers
  • TAK 733
  • Phosphatidylinositol 3-Kinases
  • Proto-Oncogene Proteins c-akt

Supplementary concepts

  • Uveal melanoma