Targeting of the MET receptor tyrosine kinase by small molecule inhibitors leads to MET accumulation by impairing the receptor downregulation.
The MET receptor tyrosine kinase is deregulated primarily via overexpression or point mutations in various human cancers and different strategies for MET inhibition are currently evaluated in clinical trials. We observed by Western blot analysis and by Flow cytometry that MET inhibition by different MET small molecule inhibitors surprisingly increases in a dose-dependent manner total MET levels in treated cells. Mechanistically, this inhibition-related MET accumulation was associated with reduced Tyr1003 phosphorylation and MET physical association with the CBL ubiquitin ligase with concomitant decrease in MET ubiquitination. These data may suggest careful consideration for design of anti-MET clinical protocols.
Department of Radiation Oncology, Inselspital, Bern University Hospital, and University of Bern, 3010 Bern, Switzerland; Department of Clinical Research, University of Bern, 3010 Bern, Switzerland.
Dominic
D
Leiser
Department of Radiation Oncology, Inselspital, Bern University Hospital, and University of Bern, 3010 Bern, Switzerland; Department of Clinical Research, University of Bern, 3010 Bern, Switzerland.
Benoît
B
Pochon
Department of Radiation Oncology, Inselspital, Bern University Hospital, and University of Bern, 3010 Bern, Switzerland; Department of Clinical Research, University of Bern, 3010 Bern, Switzerland.
Wieslawa
W
Blank-Liss
Department of Radiation Oncology, Inselspital, Bern University Hospital, and University of Bern, 3010 Bern, Switzerland; Department of Clinical Research, University of Bern, 3010 Bern, Switzerland.
Paola
P
Francica
Department of Radiation Oncology, Inselspital, Bern University Hospital, and University of Bern, 3010 Bern, Switzerland; Department of Clinical Research, University of Bern, 3010 Bern, Switzerland.
Astrid A
AA
Glück
Department of Radiation Oncology, Inselspital, Bern University Hospital, and University of Bern, 3010 Bern, Switzerland; Department of Clinical Research, University of Bern, 3010 Bern, Switzerland.
Daniel M
DM
Aebersold
Department of Radiation Oncology, Inselspital, Bern University Hospital, and University of Bern, 3010 Bern, Switzerland; Department of Clinical Research, University of Bern, 3010 Bern, Switzerland.
Yitzhak
Y
Zimmer
Department of Radiation Oncology, Inselspital, Bern University Hospital, and University of Bern, 3010 Bern, Switzerland; Department of Clinical Research, University of Bern, 3010 Bern, Switzerland. Electronic address: michaela.Medova@dkf.unibe.ch.
Michaela
M
Medová
D000818:Animals; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D000077547:Crizotinib; D015536:Down-Regulation / Q000187:drug effects*; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D008247:Lysosomes / Q000378:metabolism; D051379:Mice; D020125:Mutation, Missense; D041681:NIH 3T3 Cells; D010879:Piperazines / Q000494:pharmacology*; D059748:Proteolysis; D050721:Proto-Oncogene Proteins c-cbl / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011720:Pyrazoles / Q000494:pharmacology; D011724:Pyridazines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology*; D013450:Sulfones / Q000494:pharmacology*; D054875:Ubiquitination
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); C480541:5-((2,6-dichlorobenzyl)sulfonyl)-3-((3,5-dimethyl-4-((2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl)carbonyl)-1H-pyrrol-2-yl)methylene)-1,3-dihydro-2H-indol-2-one; C582858:EMD1214063; D007211:Indoles; D010879:Piperazines; D011720:Pyrazoles; D011724:Pyridazines; D011725:Pyridines; D011743:Pyrimidines; D013449:Sulfonamides; D013450:Sulfones; D000077547:Crizotinib; D050721:Proto-Oncogene Proteins c-cbl; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met; C067419:CBL protein, human
CBL; MET; MET Tyr1003; Receptor downregulation; Receptor ubiquitination; Small molecule tyrosine kinase inhibitor