Targeting of both the c-Met and EGFR pathways results in additive inhibition of lung tumorigenesis in transgenic mice

Laura P. Stabile, Mary E. Rothstein, Phouthone Keohavong, Diana Lenzner, Stephanie R. Land, Autumn L. Gaither-Davis, K. Jin Kim, Naftali Kaminski, Jill M. Siegfried

Research output: Contribution to journalArticlepeer-review

33 Scopus citations

Abstract

EGFR and c-Met are both overexpressed in lung cancer and initiate similar downstream signaling, which may be redundant. To determine how frequently ligands that initiate signaling of both pathways are found in lung cancer, we analyzed serum for hepatocyte growth factor (HGF), transforming growth factor-alpha, and amphiregulin (AREG) in lung cancer cases and tobacco-exposed controls. HGF and AREG were both significantly elevated in cases compared to controls, suggesting that both HGF/c-Met and AREG/EGFR pathways are frequently active. When both HGF and AREG are present in vitro, downstream signaling to MAPK and Akt in non-small cell lung cancer (NSCLC) cells can only be completely inhibited by targeting both pathways. To test if dual blockade of the pathways could better suppress lung tumorigenesis in an animal model than single blockade, mice transgenic for airway expression of human HGF were treated with inhibitors of both pathways alone and in combination after exposure to a tobacco carcinogen. Mean tumor number in the group using both the HGF neutralizing antibody L2G7 and the EGFR inhibitor gefitinib was significantly lower than with single agents. A higher tumor K-ras mutation rate was observed with L2G7 alone compared to controls, suggesting that agents targeting HGF may be less effective against mutated K-ras lung tumors. This was not observed with combination treatment. A small molecule c-Met inhibitor decreased formation of both K-ras wild-type and mutant tumors and showed additive anti-tumor effects when combined with gefitinib. Dual targeting of c-Met/EGFR may have clinical benefit for lung cancer.

Original languageEnglish (US)
Pages (from-to)2153-2170
Number of pages18
JournalCancers
Volume2
Issue number4
DOIs
StatePublished - Dec 2010

Keywords

  • EGFR
  • HGF
  • Lung cancer
  • c-Met

Fingerprint Dive into the research topics of 'Targeting of both the c-Met and EGFR pathways results in additive inhibition of lung tumorigenesis in transgenic mice'. Together they form a unique fingerprint.

Cite this