5UAB

MET Tyrosine Kinase Inhibition Enhances the Antitumor Efficacy of an HGF Antibody

5UAB の概要

• エントリーDOI: 10.2210/pdb5uab/pdb
• 関連するPDBエントリー: 5UAD 5UAF
• 分子名称: Hepatocyte growth factor receptor, N-{6-[([1,2,4]triazolo[4,3-a]pyridin-3-yl)sulfanyl]imidazo[1,2-b]pyridazin-2-yl}cyclopropanecarboxamide, GLYCEROL, ... (5 entities in total)
• 機能のキーワード: met, tyrosine kinase, inhibitor, antitumor, transferase-inhibitor complex, transferase/inhibitor
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Membrane; Single-pass type I membrane protein. Isoform 3: Secreted: P08581
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 39057.44

構造登録者

Hoffman, I.D.,Lawson, J.D. (登録日: 2016-12-19, 公開日: 2017-05-31, 最終更新日: 2024-03-06)

主引用文献

Farrell, P.J.,Matuszkiewicz, J.,Balakrishna, D.,Pandya, S.,Hixon, M.S.,Kamran, R.,Chu, S.,Lawson, J.D.,Okada, K.,Hori, A.,Mizutani, A.,Iwata, H.,de Jong, R.,Hibner, B.,Vincent, P.
MET Tyrosine Kinase Inhibition Enhances the Antitumor Efficacy of an HGF Antibody.
Mol. Cancer Ther., 16:1269-1278, 2017

PubMed 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. .

PubMed: 28341789
DOI: 10.1158/1535-7163.MCT-16-0771

実験手法

X-RAY DIFFRACTION (1.9 Å)