Combined vascular endothelial growth factor receptor and Epidermal Growth Factor Receptor (EGFR) blockade inhibits tumor growth in xenograft models of EGFR inhibitor resistance

George N. Naumov, Monique B. Nilsson, Tina Cascone, Alexandra Briggs, Oddbjorn Straume, Lars A. Akslen, Eugene Lifshits, Lauren Averett Byers, Li Xu, Hua Kang Wu, Pasi Jänne, Susumu Kobayashi, Balazs Halmos, Daniel Tenen, Xi M. Tang, Jeffrey Engelman, Beow Yeap, Judah Folkman, Bruce E. Johnson, John V. Heymach

Research output: Contribution to journalArticle

208 Scopus citations

Abstract

Purpose: The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) gefitinib and erlotinib benefit some non-small cell lung cancer (NSCLC) patients, but mostdo notrespond (primary resistance) and those who initially respond eventually progress (acquired resistance). EGFR TKI resistance is not completely understood and has been associated with certain EGFR and K-RAS mutations and MET amplification. Experimental Design: We hypothesized that dual inhibition of the vascular endothelial growth factor (VEGF) and EGFR pathways may overcome primary and acquired resistance. We investigated the VEGF receptor/EGFR TKI vandetanib, and the combination of bevacizumab and erlotinib in vivo using xenograft models of EGFR TKI sensitivity, primary resistance, and three models of acquired resistance, including models with mutated K-RAS and secondary EGFR T790M mutation. Results: Vandetanib, gefitinib, and erlotinib had similar profiles of in vitro activity and caused sustained tumor regressions in vivo in the sensitive HCC827 model. In all four resistant models, vandetanib and bevacizumab/erlotinib were significantly more effective than erlotinib or gefitinib alone. Erlotinib resistance was associated with a rise in both host and tumor-derived VEGF but not EGFR secondary mutations in the KRAS mutant-bearing A549 xenografts. Dual inhibition reduced tumor endothelial proliferation compared with VEGF or EGFR blockade alone, suggesting that the enhanced activity of dual inhibition is due at least in part to antiendothelial effects. Conclusion: These studies suggest that erlotinib resistance may be associated with a rise in both tumor cell and host stromal VEGF and that combined blockade of the VEGFR and EGFR pathways can abrogate primary or acquired resistance to EGFR TKIs. This approach merits further evaluation in NSCLC patients.

Original languageEnglish (US)
Pages (from-to)3484-3494
Number of pages11
JournalClinical Cancer Research
Volume15
Issue number10
DOIs
StatePublished - May 15 2009
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Naumov, G. N., Nilsson, M. B., Cascone, T., Briggs, A., Straume, O., Akslen, L. A., Lifshits, E., Byers, L. A., Xu, L., Wu, H. K., Jänne, P., Kobayashi, S., Halmos, B., Tenen, D., Tang, X. M., Engelman, J., Yeap, B., Folkman, J., Johnson, B. E., & Heymach, J. V. (2009). Combined vascular endothelial growth factor receptor and Epidermal Growth Factor Receptor (EGFR) blockade inhibits tumor growth in xenograft models of EGFR inhibitor resistance. Clinical Cancer Research, 15(10), 3484-3494. https://doi.org/10.1158/1078-0432.CCR-08-2904