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HGF-independent potentiation of EGFR action by c-Met

Oncogene volume 30, pages 3625–3635 (2011)Cite this article

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Abstract

The c-Met receptor is a potential therapeutic target for non-small cell lung cancer (NSCLC). Signaling interactions between c-Met and the mutant epidermal growth factor receptor (EGFR) have been studied extensively, but signaling intermediates and biological consequences of lateral signaling to c-Met in EGFR wild-type tumors are minimally understood. Our observations indicate that delayed c-Met activation in NSCLC cell lines is initiated by wild-type EGFR, the receptor most often found in NSCLC tumors. EGFR ligands induce accumulation of activated c-Met, which begins at 8 h and continues for 48 h. This effect is accompanied by an increase in c-Met expression and phosphorylation of critical c-Met tyrosine residues without activation of mitogen-activated protein kinase (MAPK) or Akt. Gene transcription is required for delayed c-Met activation; however, phosphorylation of c-Met by EGFR occurs without production of hepatocyte growth factor (HGF) or another secreted factor, supporting a ligand-independent mechanism. Lateral signaling is blocked by two selective c-Met tyrosine kinase inhibitors (TKIs), PF2341066 and SU11274, or with gefitinib, an EGFR TKI, suggesting kinase activity of both receptors is required for this effect. Prolonged c-Src phosphorylation is observed, and c-Src pathway is essential for EGFR to c-Met communication. Pretreatment with pan-Src family kinase inhibitors, PP2 and dasatinib, abolishes delayed c-Met phosphorylation. A c-Src dominant-negative construct reduces EGF-induced c-Met phosphorylation compared with control, further confirming a c-Src requirement. Inhibition of c-Met with PF2341066 and siRNA decreases EGF-induced phenotypes of invasion by ∼86% and motility by ∼81%, suggesting that a novel form of c-Met activation is utilized by EGFR to maximize these biological effects. Combined targeting of c-Met and EGFR leads to increased xenograft antitumor activity, demonstrating that inhibition of downstream and lateral signaling from the EGFR-c-Src–c-Met axis might be effective in treatment of NSCLC.

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Abbreviations

EGF:

epidermal growth factor

EGFR:

epidermal growth factor receptor

HGF:

hepatocyte growth factor

NSCLC:

non-small cell lung cancer

SFK:

Src family kinase

TKI:

tyrosine kinase inhibitor

TGF-α:

transforming growth factor-α

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Acknowledgements

This work was supported by NIH grant R01 CA79882 to JMS from the National Cancer Institute and by a Predoctoral Fellowship in Pharmacology by Pharmaceutical Research and Manufacturers of America Foundation awarded to Austin M Dulak. We would like to thank Pfizer for kindly providing PF2341066.

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Authors and Affiliations

  1. Department of Pharmacology & Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA

    A M Dulak, C T Gubish, L P Stabile, C Henry & J M Siegfried

  2. University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA, USA

    J M Siegfried

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  1. A M Dulak
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  2. C T Gubish
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  3. L P Stabile
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Correspondence to J M Siegfried.

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Dulak, A., Gubish, C., Stabile, L. et al. HGF-independent potentiation of EGFR action by c-Met. Oncogene 30, 3625–3635 (2011). https://doi.org/10.1038/onc.2011.84

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