Abstract

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.

Highlights

  • MET receptor tyrosine kinase (RTK) and its ligand hepatocyte growth factory (HGF) regulate biological processes involved in tumor initiation, progression, and metastasis, including cell proliferation, survival, migration, invasion, and angiogenesis

  • Discovery of selective MET inhibitors with slow off rate The compound shown in Fig. 1 is derived from the imidazopyridazine chemical series, which is a novel hinge-binder class of MET inhibitors described in WO2010/019899A1

  • In a second U-87MG xenograft study, we evaluated if the synergy was specific for Compound 1 or could be observed with other MET tyrosine kinase inhibitor (TKI)

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Summary

Introduction

MET receptor tyrosine kinase (RTK) and its ligand hepatocyte growth factory (HGF) regulate biological processes involved in tumor initiation, progression, and metastasis, including cell proliferation, survival, migration, invasion, and angiogenesis (for recent reviews, see refs. 1–3). MET receptor tyrosine kinase (RTK) and its ligand hepatocyte growth factory (HGF) regulate biological processes involved in tumor initiation, progression, and metastasis, including cell proliferation, survival, migration, invasion, and angiogenesis Upon stimulation by HGF, the MET receptor dimerizes, transphosphorylates, and recruits proteins that activate MAPK, STAT3, and PI3K/AKT pathways. Pathway activation is terminated when phosphorylated MET is internalized and degraded [4, 5]. HGF/MET signaling evokes changes in gene transcription and protein stability setting up a complex. Note: Supplementary data for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/). Pandya: Illumina, Inc., San Diego, CA 92122

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