Met kinase inhibitor E7050 reverses three different mechanisms of hepatocyte growth factor-induced tyrosine kinase inhibitor resistance in EGFR mutant lung cancer.

Abstract

PURPOSE:

Hepatocyte growth factor (HGF) induces resistance to reversible and irreversible epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKI) in EGFR mutant lung cancer cells by activating Met and the downstream phosphoinositide 3-kinase (PI3K)/Akt pathway. Moreover, continuous exposure to HGF accelerates the emergence of EGFR-TKI-resistant clones. We assayed whether a new Met kinase inhibitor, E7050, which is currently being evaluated in clinical trials, could overcome these three mechanisms of resistance to EGFR-TKIs.

EXPERIMENTAL DESIGN:

The effects of E7050 on HGF-induced resistance to reversible (gefitinib), irreversible (BIBW2992), and mutant-selective (WZ4002) EGFR-TKIs were determined using the EGFR mutant human lung cancer cell lines PC-9 and HCC827 with an exon 19 deletion and H1975 with an T790M secondary mutation. PC-9 cells were mixed with HGF-producing fibroblasts, MRC-5 cells, and subcutaneously inoculated into severe combined immunodeficient mice, and the therapeutic effects of E7050 plus gefitinib were assayed.

RESULTS:

E7050 circumvented resistance to all of the reversible, irreversible, and mutant-selective EGFR-TKIs induced by exogenous and/or endogenous HGF in EGFR mutant lung cancer cell lines, by blocking the Met/Gab1/PI3K/Akt pathway in vitro. E7050 also prevented the emergence of gefitinib-resistant HCC827 cells induced by continuous exposure to HGF. In the in vivo model, E7050 plus gefitinib resulted in marked regression of tumor growth associated with inhibition of Akt phosphorylation in cancer cells.

CONCLUSIONS:

A new Met kinase inhibitor, E7050, reverses the three HGF-induced mechanisms of gefitinib resistance, suggesting that E7050 may overcome HGF-induced resistance to gefitinib and next-generation EGFR-TKIs.

• Authors: Wei Wang, Qi Li, Shinji Takeuchi, Tadaaki Yamada, Hitomi Koizumi, Takahiro Nakamura, Kunio Matsumoto, Naofumi Mukaida, Yasuhiko Nishioka, Saburo Sone, Takayuki Nakagawa, Toshimitsu Uenaka, Seiji Yano
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 18 Issue 6 Pg. 1663-71 (Mar 15 2012) ISSN: 1557-3265 [Electronic] United States
• PMID: 22317763 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Aminopyridines
• Antineoplastic Agents
• 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
• Hepatocyte Growth Factor
• ErbB Receptors
• Protein-Tyrosine Kinases
• Gefitinib

Topics

• Aminopyridines (pharmacology)
• Animals
• Antineoplastic Agents (pharmacology)
• Cell Line, Tumor
• Drug Resistance, Neoplasm (drug effects)
• ErbB Receptors (genetics)
• Female
• Gefitinib
• Hepatocyte Growth Factor (pharmacology)
• Humans
• Lung Neoplasms (drug therapy, genetics)
• Mice
• Mice, SCID
• Mutation
• Piperazines (pharmacology)
• Protein-Tyrosine Kinases (antagonists & inhibitors)
• Quinazolines (pharmacology)
• Xenograft Model Antitumor Assays