Open AccessEnhanced anti‐angiogenic effect of E 7820 in combination with erlotinib in epidermal growth factor receptor–tyrosine kinase inhibitor‐resistant non‐small‐cell lung cancer xenograft models
Author(s) -
Ito Ken,
Semba Taro,
Uenaka Toshimitsu,
Wakabayashi Toshiaki,
Asada Makoto,
Funahashi Yasuhiro
Publication year - 2014
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/cas.12450
Subject(s) - erlotinib , t790m , epidermal growth factor receptor , cancer research , angiogenesis , erlotinib hydrochloride , tyrosine kinase inhibitor , egfr inhibitors , lung cancer , pten , cd31 , tyrosine kinase , medicine , apoptosis , pharmacology , biology , cancer , gefitinib , pathology , receptor , pi3k/akt/mtor pathway , biochemistry
Most non‐small‐cell lung cancers ( NSCLC s) harboring activating mutations in the epidermal growth factor receptor ( EGFR ) are initially responsive to EGFR tyrosine kinase inhibitors ( EGFR ‐ TKI s); however, they invariably develop resistance to these drugs. E 7820 is an angiogenesis inhibitor that decreases integrin‐α2 expression and is currently undergoing clinical trials. We investigated whether E 7820 in combination with erlotinib, an EGFR ‐ TKI , could overcome EGFR ‐ TKI ‐resistance in the NSCLC cell lines A 549 ( KRAS ; G12S), H1975 ( EGFR ; L 858R/ T 790M), and H 1650 ( PTEN ; loss, EGFR ; exon 19 deletion), which are resistant to erlotinib. Immunohistochemical analysis was carried out in xenografted tumors to investigate anti‐angiogenesis activity and endothelial cell apoptosis levels by endothelial cell marker CD 31 and TUNEL staining, respectively. Treatment with E 7820 (50 mg/kg) with erlotinib (60 mg/kg) showed a synergistic antitumor effect in three xenograft models. Immunohistochemical analysis indicated that combined treatment with E7820 and erlotinib significantly decreased microvessel density and increased apoptosis of tumor‐associated endothelial cells compared with use of only one of the agents. This combination increased apoptosis in HUVEC s through activation of both intrinsic and extrinsic apoptosis pathways in vitro . The combination of E 7820 with erlotinib is an alternative strategy to overcome erlotinib resistance in NSCLC by enhancement of the anti‐angiogenic activity of E 7820.