The novel ATP-competitive inhibitor of the MET hepatocyte growth factor receptor EMD1214063 displays inhibitory activity against selected MET-mutated variants.
The receptor tyrosine kinase MET is a prime target in clinical oncology due to its aberrant activation and involvement in the pathogenesis of a broad spectrum of malignancies. Similar to other targeted kinases, primary and secondary mutations seem to represent an important resistance mechanism to MET inhibitors. Here, we report the biologic activity of a novel MET inhibitor, EMD1214063, on cells that ectopically express the mutated MET variants M1268T, Y1248H, H1112Y, L1213V, H1112L, V1110I, V1206L, and V1238I. Our results show a dose-dependent decrease in MET autophosphorylation in response to EMD1214063 in five of the eight cell lines (IC50 2-43 nmol/L). Blockade of MET by EMD1214063 was accompanied by a reduced activation of downstream effectors in cells expressing EMD1214063-sensitive mutants. In all sensitive mutant-expressing lines, EMD1214063 altered cell-cycle distribution, primarily with an increase in G1 phase. EMD1214063 strongly influenced MET-driven biologic functions, such as cellular morphology, MET-dependent cell motility, and anchorage-independent growth. To assess the in vivo efficacy of EMD1214063, we used a xenograft tumor model in immunocompromised mice bearing NIH3T3 cells expressing sensitive and resistant MET-mutated variants. Animals were randomized for the treatment with EMD1214063 (50 mg/kg/d) or vehicle only. Remarkably, five days of EMD1214063 treatment resulted in a complete regression of the sensitive H1112L-derived tumors, whereas tumor growth remained unaffected in mice with L1213V tumors and in vehicle-treated animals. Collectively, the current data identifies EMD1214063 as a potent MET small-molecule inhibitor with selective activity towards mutated MET variants.
Corresponding Author: Michaela Medová, Radiation Oncology, Department of Clinical Research, University of Bern/Inselspital, MEM-E815, Murtenstrassse 35, 3010 Bern, Switzerland. michaela.medova@dkf.unibe.ch.
Michaela
M
Medová
Benoît
B
Pochon
Bruno
B
Streit
Wieslawa
W
Blank-Liss
Paola
P
Francica
Deborah
D
Stroka
Adrian
A
Keogh
Daniel M
DM
Aebersold
Andree
A
Blaukat
Friedhelm
F
Bladt
Yitzhak
Y
Zimmer
D000818:Animals; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D005260:Female; D014644:Genetic Variation; D006801:Humans; D051379:Mice; D041681:NIH 3T3 Cells; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D017354:Point Mutation; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000378:metabolism; D011724:Pyridazines / Q000008:administration & dosage / Q000494:pharmacology*; D011743:Pyrimidines / Q000008:administration & dosage / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
C582858:EMD1214063; D047428:Protein Kinase Inhibitors; D011724:Pyridazines; D011743:Pyrimidines; D019859:Proto-Oncogene Proteins c-met