MET oncogene inhibition as a potential target of therapy for uveal melanomas.
PURPOSE. The purposes of this study were to investigate the frequency of MET activation in uveal melanomas (UMs), to study the potential molecular mechanism for its activation, and to assess the utility of MET inhibition as a potential therapy for UM. METHODS. The frequency of MET activation in UMs was studied by using immunohistochemistry and Western blot analysis in 46 primary UMs and six UM cell lines. Sequencing was used for detection of activating mutations in the MET gene, and the effect of selective MET inhibition was assessed by cell proliferation and migration assays. RESULTS. The results showed that the majority (82.5%) of the 46 UMs expressed activated MET protein. Three of the UM cell lines, C918, 92.1, and MEL202, showed strong MET and pMET expression, whereas the other three showed weaker expression. Sequence analysis identified no activating mutations in MET in any of the 22 tumors or in the six UM cell lines. Selective MET blocking showed inhibition of tumor cell proliferation at an IC(50) ranging from 2.5 to 5.2 microM. A significant inhibition of UM cell migration was also observed starting at 1.25 microM. CONCLUSIONS. The results indicate that MET is activated in a significant number of UMs and also that MET activation in UMs is most likely through indirect gene activation rather than copy number alteration or mutation involving the MET gene. MET inhibition could be a target of therapy for UM.
Abdel-Rahman
Mohamed H
MH
Department of Ophthalmology, The Ohio State University, Columbus, Ohio, USA. mohamed.abdel-rahman@osumc.edu
Boru
Getachew
G
Massengill
James
J
Salem
Manar M
MM
Davidorf
Frederick H
FH
D015153:Blotting, Western; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004273:DNA, Neoplasm / Q000032:analysis; D006801:Humans; D007150:Immunohistochemistry; D007211:Indoles / Q000494:pharmacology*; D008545:Melanoma / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D010766:Phosphorylation; D010879:Piperazines / Q000494:pharmacology*; D020641:Polymorphism, Single Nucleotide; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D017978:Receptors, Growth Factor / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013449:Sulfonamides / Q000494:pharmacology*; D015533:Transcriptional Activation; D014604:Uveal Neoplasms / Q000378:metabolism / Q000473:pathology / Q000628:therapy*
C478479:((3Z)-N-(3-chlorophenyl)-3-((3,5-dimethyl-4-((4-methylpiperazin-1-yl)carbonyl)-1H-pyrrol-2-yl)methylene)-N-methyl-2-oxo-2,3-dihydro-1H-indole-5-sulfonamide); D004273:DNA, Neoplasm; D007211:Indoles; D010879:Piperazines; D012333:RNA, Messenger; D017978:Receptors, Growth Factor; D013449:Sulfonamides; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met; D020794:Receptor Protein-Tyrosine Kinases