Open Access

Bevacizumab counteracts VEGF-dependent resistance to erlotinib in an EGFR-mutated NSCLC xenograft model

  • Authors:
    • Chinami Masuda
    • Mieko Yanagisawa
    • Keigo Yorozu
    • Mitsue Kurasawa
    • Koh Furugaki
    • Nobuyuki Ishikura
    • Toshiki Iwai
    • Masamichi Sugimoto
    • Kaname Yamamoto
  • View Affiliations

  • Published online on: June 8, 2017     https://doi.org/10.3892/ijo.2017.4036
  • Pages:425-434
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Abstract

Erlotinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), shows superior efficacy in patients with non-small cell lung cancer (NSCLC) harboring activating EGFR mutations (EGFR Mut+). However, almost all tumors eventually develop resistance to erlotinib. Recently, the Phase II JO25567 study reported significant prolongation of progression-free survival (PFS) by erlotinib plus bevacizumab combination compared with erlotinib in EGFR Mut+ NSCLC. Herein, we established a preclinical model which became refractory to erlotinib after long-term administration and elucidated the mode of action of this combination. In this model, tumor regrowth occurred after remarkable shrinkage by erlotinib; regrowth was successfully inhibited by erlotinib plus bevacizumab. Tumor vascular endothelial growth factor (VEGF) was greatly reduced by erlotinib in the erlotinib-sensitive phase but significantly increased in the erlotinib-refractory phase despite continued treatment with erlotinib. Although EGFR phosphorylation remained suppressed in the erlotinib-refractory phase, phosphorylated extracellular signal-regulated kinase (pERK), phosphorylated AKT, and phosphorylated signal transducer and activator of transcription 3 (pSTAT3) were markedly higher than in the erlotinib-sensitive phase; among these, pERK was suppressed by erlotinib plus bevacizumab. MVD was decreased significantly more with erlotinib plus bevacizumab than with each drug alone. In conclusion, the erlotinib plus bevacizumab combination demonstrated promising efficacy in the B901L xenograft model of EGFR Mut+ NSCLC. Re-induction of VEGF and subsequent direct or indirect VEGF-dependent tumor growth was suggested as a major mechanism of erlotinib resistance, and erlotinib plus bevacizumab achieved remarkably prolonged antitumor activity in this model.

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August 2017
Volume 51 Issue 2

Print ISSN: 1019-6439
Online ISSN:1791-2423

2016 Impact Factor: 3.079
Ranked #33/217 Oncology
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APA
Masuda, C., Yanagisawa, M., Yorozu, K., Kurasawa, M., Furugaki, K., Ishikura, N. ... Yamamoto, K. (2017). Bevacizumab counteracts VEGF-dependent resistance to erlotinib in an EGFR-mutated NSCLC xenograft model. International Journal of Oncology, 51, 425-434. https://doi.org/10.3892/ijo.2017.4036
MLA
Masuda, C., Yanagisawa, M., Yorozu, K., Kurasawa, M., Furugaki, K., Ishikura, N., Iwai, T., Sugimoto, M., Yamamoto, K."Bevacizumab counteracts VEGF-dependent resistance to erlotinib in an EGFR-mutated NSCLC xenograft model". International Journal of Oncology 51.2 (2017): 425-434.
Chicago
Masuda, C., Yanagisawa, M., Yorozu, K., Kurasawa, M., Furugaki, K., Ishikura, N., Iwai, T., Sugimoto, M., Yamamoto, K."Bevacizumab counteracts VEGF-dependent resistance to erlotinib in an EGFR-mutated NSCLC xenograft model". International Journal of Oncology 51, no. 2 (2017): 425-434. https://doi.org/10.3892/ijo.2017.4036