MET Tyrosine Kinase Inhibition Enhances the Antitumor Efficacy of an HGF Antibody.
Receptor tyrosine kinase therapies have proven to be efficacious in specific cancer patient populations; however, a significant limitation of tyrosine kinase inhibitor (TKI) treatment is the emergence of resistance mechanisms leading to a transient, partial, or complete lack of response. Combination therapies using agents with synergistic activity have potential to improve response and reduce acquired resistance. Chemoreagent or TKI treatment can lead to increased expression of hepatocyte growth factor (HGF) and/or MET, and this effect correlates with increased metastasis and poor prognosis. Despite MET's role in resistance and cancer biology, MET TKI monotherapy has yielded disappointing clinical responses. In this study, we describe the biological activity of a selective, oral MET TKI with slow off-rate and its synergistic antitumor effects when combined with an anti-HGF antibody. We evaluated the combined action of simultaneously neutralizing HGF ligand and inhibiting MET kinase activity in two cancer xenograft models that exhibit autocrine HGF/MET activation. The combination therapy results in additive antitumor activity in KP4 pancreatic tumors and synergistic activity in U-87MG glioblastoma tumors. Pharmacodynamic characterization of biomarkers that correlate with combination synergy reveal that monotherapies induce an increase in the total MET protein, whereas combination therapy significantly reduces total MET protein levels and phosphorylation of 4E-BP1. These results hold promise that dual targeting of HGF and MET by combining extracellular ligand inhibitors with intracellular MET TKIs could be an effective intervention strategy for cancer patients who have acquired resistance that is dependent on total MET protein.Mol Cancer Ther; 16(7); 1269-78. ©2017 AACR.
Department of Biological Sciences, Takeda California, San Diego, California. pw2h@att.net.
Pamela J
PJ
Farrell
Department of Biological Sciences, Takeda California, San Diego, California.
Jennifer
J
Matuszkiewicz
Department of Biological Sciences, Takeda California, San Diego, California.
Deepika
D
Balakrishna
Department of Biological Sciences, Takeda California, San Diego, California.
Shweta
S
Pandya
Department of Biological Sciences, Takeda California, San Diego, California.
Mark S
MS
Hixon
Department of Biological Sciences, Takeda California, San Diego, California.
Ruhi
R
Kamran
Department of Chemistry, Takeda California, San Diego, California.
Shaosong
S
Chu
Department of Computational Sciences and Crystallography, Takeda California, San Diego, California.
J David
JD
Lawson
Pharmaceutical Research Division, Takeda Pharmaceutical Companies Ltd, Shonan, Japan.
Kengo
K
Okada
Pharmaceutical Research Division, Takeda Pharmaceutical Companies Ltd, Shonan, Japan.
Akira
A
Hori
Pharmaceutical Research Division, Takeda Pharmaceutical Companies Ltd, Shonan, Japan.
Akio
A
Mizutani
Pharmaceutical Research Division, Takeda Pharmaceutical Companies Ltd, Shonan, Japan.
Hidehisa
H
Iwata
Department of Biological Sciences, Takeda California, San Diego, California.
Ron
R
de Jong
Oncology Biology, Takeda Boston, Cambridge, Massachusetts.
Barbara
B
Hibner
Department of Biological Sciences, Takeda California, San Diego, California.
Patrick
P
Vincent
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000818:Animals; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D004357:Drug Synergism; D005909:Glioblastoma / Q000188:drug therapy* / Q000235:genetics; D017228:Hepatocyte Growth Factor / Q000037:antagonists & inhibitors / Q000235:genetics*; D006801:Humans; D051379:Mice; D010750:Phosphoproteins / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage*; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors / Q000235:genetics*; D054852:Small Molecule Libraries / Q000008:administration & dosage*; D023041:Xenograft Model Antitumor Assays
D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; C087000:EIF4EBP1 protein, human; C066855:HGF protein, human; D010750:Phosphoproteins; D047428:Protein Kinase Inhibitors; D054852:Small Molecule Libraries; D017228:Hepatocyte Growth Factor; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met