title: Impact of bevacizumab in combination with erlotinib on EGFR-mutated non-small cell lung cancer xenograft models with T790M mutation or MET amplification.
abstract: 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.
authors.affiliation: Product Research Department, Kamakura Research Laboratories, Chugai Pharmaceutical, Kanagawa, Japan.
authors.forename: Koh
authors.initials: K
authors.lastname: Furugaki
authors.affiliation: Product Research Department, Kamakura Research Laboratories, Chugai Pharmaceutical, Kanagawa, Japan.
authors.forename: Junko
authors.initials: J
authors.lastname: Fukumura
authors.affiliation: Product Research Department, Kamakura Research Laboratories, Chugai Pharmaceutical, Kanagawa, Japan.
authors.forename: Toshiki
authors.initials: T
authors.lastname: Iwai
authors.affiliation: Product Research Department, Kamakura Research Laboratories, Chugai Pharmaceutical, Kanagawa, Japan.
authors.forename: Keigo
authors.initials: K
authors.lastname: Yorozu
authors.affiliation: Product Research Department, Kamakura Research Laboratories, Chugai Pharmaceutical, Kanagawa, Japan.
authors.forename: Mitsue
authors.initials: M
authors.lastname: Kurasawa
authors.affiliation: Product Research Department, Kamakura Research Laboratories, Chugai Pharmaceutical, Kanagawa, Japan.
authors.forename: Mieko
authors.initials: M
authors.lastname: Yanagisawa
authors.affiliation: Product Research Department, Kamakura Research Laboratories, Chugai Pharmaceutical, Kanagawa, Japan.
authors.forename: Yoichiro
authors.initials: Y
authors.lastname: Moriya
authors.affiliation: Product Research Department, Kamakura Research Laboratories, Chugai Pharmaceutical, Kanagawa, Japan.
authors.forename: Kaname
authors.initials: K
authors.lastname: Yamamoto
authors.affiliation: Division of Thoracic Surgery, Department of Surgery, Kinki University Faculty of Medicine, Osaka, Japan.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Suda
authors.affiliation: Division of Thoracic Surgery, Department of Surgery, Kinki University Faculty of Medicine, Osaka, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Mizuuchi
authors.affiliation: Division of Thoracic Surgery, Department of Surgery, Kinki University Faculty of Medicine, Osaka, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Mitsudomi
authors.affiliation: Product Research Department, Kamakura Research Laboratories, Chugai Pharmaceutical, Kanagawa, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Harada
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D000068258:Bevacizumab / Q000008:administration & dosage; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000473:pathology*; D045744:Cell Line, Tumor; D066246:ErbB Receptors / Q000235:genetics; D000069347:Erlotinib Hydrochloride / Q000008:administration & dosage; D005784:Gene Amplification; D018773:Genes, erbB-1; D006801:Humans; D015151:Immunoblotting; D008175:Lung Neoplasms / Q000235:genetics / Q000473:pathology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009154:Mutation; D016133:Polymerase Chain Reaction; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000068258:Bevacizumab; D000069347:Erlotinib Hydrochloride; C541485:EGFR protein, mouse; D066246:ErbB Receptors; D019859:Proto-Oncogene Proteins c-met
keywords: MET amplification; T790M mutation; bevacizumab; erlotinib