title: Antitumor effects of the investigational selective MEK inhibitor TAK733 against cutaneous and uveal melanoma cell lines.
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.
authors.affiliation: Department of Medicine, Division of Hematology/Oncology, University of California Los Angeles (UCLA), Los Angeles, CA, USA.
authors.forename: Erika
authors.initials: E
authors.lastname: von Euw
authors.forename: Mohammad
authors.initials: M
authors.lastname: Atefi
authors.forename: Narsis
authors.initials: N
authors.lastname: Attar
authors.forename: Connie
authors.initials: C
authors.lastname: Chu
authors.forename: Sybil
authors.initials: S
authors.lastname: Zachariah
authors.forename: Barry L
authors.initials: BL
authors.lastname: Burgess
authors.forename: Stephen
authors.initials: S
authors.lastname: Mok
authors.forename: Charles
authors.initials: C
authors.lastname: Ng
authors.forename: Deborah Jl
authors.initials: DJ
authors.lastname: Wong
authors.forename: Bartosz
authors.initials: B
authors.lastname: Chmielowski
authors.forename: David I
authors.initials: DI
authors.lastname: Lichter
authors.forename: Richard C
authors.initials: RC
authors.lastname: Koya
authors.forename: Tara A
authors.initials: TA
authors.lastname: McCannel
authors.forename: Elena
authors.initials: E
authors.lastname: Izmailova
authors.forename: Antoni
authors.initials: A
authors.lastname: Ribas
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D006801:Humans; D020128:Inhibitory Concentration 50; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008545:Melanoma / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011728:Pyridones / Q000494:pharmacology*; D011744:Pyrimidinones / Q000494:pharmacology*; D011849:Radioactive Tracers; D015398:Signal Transduction / Q000187:drug effects; D012878:Skin Neoplasms / Q000378:metabolism*; D014604:Uveal Neoplasms / Q000378:metabolism*; D000098943:Uveal Melanoma
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011728:Pyridones; D011744:Pyrimidinones; D011849:Radioactive Tracers; C558666:TAK 733; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt