Dual inhibition of Met kinase and angiogenesis to overcome HGF-induced EGFR-TKI resistance in EGFR mutant lung cancer.

Abstract

Acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) is a serious problem in the management of EGFR mutant lung cancer. We recently reported that hepatocyte growth factor (HGF) induces resistance to EGFR-TKIs by activating the Met/PI3K pathway. HGF is also known to induce angiogenesis in cooperation with vascular endothelial growth factor (VEGF), which is an important therapeutic target in lung cancer. Therefore, we hypothesized that dual inhibition of HGF and VEGF may be therapeutically useful for controlling HGF-induced EGFR-TKI-resistant lung cancer. We found that a dual Met/VEGF receptor 2 kinase inhibitor, E7050, circumvented HGF-induced EGFR-TKI resistance in EGFR mutant lung cancer cell lines by inhibiting the Met/Gab1/PI3K/Akt pathway in vitro. HGF stimulated VEGF production by activation of the Met/Gab1 signaling pathway in EGFR mutant lung cancer cell lines, and E7050 showed an inhibitory effect. In a xenograft model, tumors produced by HGF-transfected Ma-1 (Ma-1/HGF) cells were more angiogenic than vector control tumors and showed resistance to gefitinib. E7050 alone inhibited angiogenesis and retarded growth of Ma-1/HGF tumors. E7050 combined with gefitinib induced marked regression of tumor growth. Moreover, dual inhibition of HGF and VEGF by neutralizing antibodies combined with gefitinib also markedly regressed tumor growth. These results indicate the therapeutic rationale of dual targeting of HGF-Met and VEGF-VEGF receptor 2 for overcoming HGF-induced EGFR-TKI resistance in EGFR mutant lung cancer.

• Authors: Shinji Takeuchi, Wei Wang, Qi Li, Tadaaki Yamada, Kenji Kita, Ivan S Donev, Takahiro Nakamura, Kunio Matsumoto, Eiji Shimizu, Yasuhiko Nishioka, Saburo Sone, Takayuki Nakagawa, Toshimitsu Uenaka, Seiji Yano
• Journal: The American journal of pathology (Am J Pathol) Vol. 181 Issue 3 Pg. 1034-43 (Sep 2012) ISSN: 1525-2191 [Electronic] United States
• PMID: 22789825 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Chemical References

• Aminopyridines
• Antibodies
• N-(2-fluoro-4-((2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)carbonylaminopyridin-4-yl)oxy)phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide
• Piperazines
• Quinazolines
• Vascular Endothelial Growth Factor A
• Hepatocyte Growth Factor
• ErbB Receptors
• MET protein, human
• Proto-Oncogene Proteins c-met
• Vascular Endothelial Growth Factor Receptor-2
• Gefitinib

Topics

• Aminopyridines (pharmacology, therapeutic use)
• Animals
• Antibodies (pharmacology)
• Antibody Specificity (drug effects)
• Cell Line, Tumor
• Drug Resistance, Neoplasm (drug effects)
• ErbB Receptors (genetics, metabolism)
• Gefitinib
• Hepatocyte Growth Factor (antagonists & inhibitors, metabolism, pharmacology)
• Humans
• Lung Neoplasms (blood supply, enzymology, pathology)
• Mice
• Models, Biological
• Mutation (genetics)
• Neovascularization, Pathologic (drug therapy, pathology)
• Piperazines (pharmacology, therapeutic use)
• Proto-Oncogene Proteins c-met (antagonists & inhibitors, metabolism)
• Quinazolines (pharmacology)
• Vascular Endothelial Growth Factor A (antagonists & inhibitors, biosynthesis)
• Vascular Endothelial Growth Factor Receptor-2 (antagonists & inhibitors, metabolism)
• Xenograft Model Antitumor Assays