Bevacizumab counteracts VEGF-dependent resistance to erlotinib in an EGFR-mutated NSCLC xenograft model
| Autor: | Mieko Yanagisawa, Koh Furugaki, Kaname Yamamoto, Masamichi Sugimoto, Mitsue Kurasawa, Keigo Yorozu, Nobuyuki Ishikura, Chinami Masuda, Toshiki Iwai |
|---|---|
| Rok vydání: | 2017 |
| Předmět: |
Vascular Endothelial Growth Factor A
0301 basic medicine Oncology erlotinib Cancer Research medicine.medical_specialty Bevacizumab medicine.drug_class bevacizumab Disease-Free Survival Tyrosine-kinase inhibitor Erlotinib Hydrochloride Mice 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Carcinoma Non-Small-Cell Lung Cell Line Tumor Internal medicine Antineoplastic Combined Chemotherapy Protocols medicine Animals Humans heterocyclic compounds Epidermal growth factor receptor neoplasms biology Oncogene business.industry Cancer Articles Cell cycle medicine.disease Xenograft Model Antitumor Assays VEGF respiratory tract diseases ErbB Receptors Vascular endothelial growth factor 030104 developmental biology chemistry Drug Resistance Neoplasm 030220 oncology & carcinogenesis Mutation biology.protein Erlotinib EGFR mutation business medicine.drug |
| Zdroj: | International Journal of Oncology |
| ISSN: | 1791-2423 1019-6439 |
| DOI: | 10.3892/ijo.2017.4036 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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