Cancers 2010, 2(4), 2153-2170; doi:10.3390/cancers2042153
Article

Targeting of Both the c-Met and EGFR Pathways Results in Additive Inhibition of Lung Tumorigenesis in Transgenic Mice

Laura P. Stabile 1,6 email, Mary E. Rothstein 1 email, Phouthone Keohavong 2,6 email, Diana Lenzner 3 email, Stephanie R. Land 3,6 email, Autumn L. Gaither-Davis 1,6 email, K. Jin Kim 4 email, Naftali Kaminski 5,6 email and Jill M. Siegfried 1,6,* email
1 Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA 15213, USA 2 Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA 15213, USA 3 Department of Biostatistics, University of Pittsburgh, Pittsburgh, PA 15213, USA 4 Galaxy Biotech, LLC, Sunnyvale, CA 94089, USA 5 Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA 6 Lung and Thoracic Malignancy Program, University of Pittsburgh, Pittsburgh, PA 15213, USA
* Author to whom correspondence should be addressed.
Received: 20 October 2010; in revised form: 25 November 2010 / Accepted: 21 December 2010 / Published: 22 December 2010
(This article belongs to the Special Issue Lung Cancer)
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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.
Keywords: lung cancer; EGFR; HGF; c-Me

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Cite This Article

MDPI and ACS Style

Stabile, L.P.; Rothstein, M.E.; Keohavong, P.; Lenzner, D.; Land, S.R.; Gaither-Davis, A.L.; Kim, K.J.; Kaminski, N.; Siegfried, J.M. Targeting of Both the c-Met and EGFR Pathways Results in Additive Inhibition of Lung Tumorigenesis in Transgenic Mice. Cancers 2010, 2, 2153-2170.

AMA Style

Stabile LP, Rothstein ME, Keohavong P, Lenzner D, Land SR, Gaither-Davis AL, Kim KJ, Kaminski N, Siegfried JM. Targeting of Both the c-Met and EGFR Pathways Results in Additive Inhibition of Lung Tumorigenesis in Transgenic Mice. Cancers. 2010; 2(4):2153-2170.

Chicago/Turabian Style

Stabile, Laura P.; Rothstein, Mary E.; Keohavong, Phouthone; Lenzner, Diana; Land, Stephanie R.; Gaither-Davis, Autumn L.; Kim, K. Jin; Kaminski, Naftali; Siegfried, Jill M. 2010. "Targeting of Both the c-Met and EGFR Pathways Results in Additive Inhibition of Lung Tumorigenesis in Transgenic Mice." Cancers 2, no. 4: 2153-2170.

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