Impact of bevacizumab in combination with erlotinib onEGFR-mutated non-small cell lung cancer xenograft models with T790M mutation orMETamplification
| Autor: | Junko Fukumura, Naoki Harada, Koh Furugaki, Kaname Yamamoto, Mitsue Kurasawa, Keigo Yorozu, Mieko Yanagisawa, Kenichi Suda, Yoichiro Moriya, Toshiki Iwai, Tetsuya Mitsudomi, Hiroshi Mizuuchi |
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| Rok vydání: | 2015 |
| Předmět: |
0301 basic medicine
Cancer Research biology Bevacizumab medicine.drug_class business.industry medicine.disease Tyrosine-kinase inhibitor respiratory tract diseases 03 medical and health sciences T790M 030104 developmental biology 0302 clinical medicine Oncology 030220 oncology & carcinogenesis Cancer research biology.protein medicine Epidermal growth factor receptor Erlotinib Signal transduction Erlotinib Hydrochloride business Lung cancer medicine.drug |
| Zdroj: | International Journal of Cancer. 138:1024-1032 |
| ISSN: | 0020-7136 |
| Popis: | Erlotinib (ERL), an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, shows notable efficacy against non-small cell lung cancer (NSCLC) harboring EGFR mutations. Bevacizumab (BEV), a humanized monoclonal antibody to vascular endothelial cell growth factor (VEGF), in combination with ERL (BEV+ERL) significantly extended progression-free survival in patients with EGFR-mutated NSCLC compared with ERL alone. However, the efficacy of BEV+ERL against EGFR-mutated NSCLC harboring T790M mutation or MET amplification, is unclear. Here, we examined the antitumor activity of BEV+ERL in four xenograft models of EGFR-mutated NSCLC (three harboring ERL resistance mutations). In the HCC827 models (exon 19 deletion: DEL), ERL significantly inhibited tumor growth by blocking EGFR signal transduction. Although there was no difference between ERL and BEV+ERL in maximum tumor growth inhibition, BEV+ERL significantly suppressed tumor regrowth during a drug-cessation period. In the HCC827-EPR model (DEL+T790M) and HCC827-vTR model (DEL+MET amplification), ERL reduced EGFR signal transduction and showed less pronounced but still significant tumor growth inhibition than in the HCC827 model. In these models, tumor growth inhibition was significantly stronger with BEV+ERL than with each single agent. In the NCI-H1975 model (L858R+T790M), ERL did not inhibit growth or EGFR signal transduction, and BEV+ERL did not inhibit growth more than BEV. BEV alone significantly decreased microvessel density in each tumor. In conclusion, addition of BEV to ERL did not enhance antitumor activity in primarily ERL-resistant tumors with T790M mutation; however, BEV+ERL enhanced antitumor activity in T790M mutation- or MET amplification-positive tumors as long as their growth remained significantly suppressed by ERL. |
| Databáze: | OpenAIRE |
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