Enhanced anti-angiogenic effect of E7820 in combination with erlotinib in epidermal growth factor receptor-tyrosine kinase inhibitor-resistant non-small-cell lung cancer xenograft models.

Abstract

Most non-small-cell lung cancers (NSCLCs) harboring activating mutations in the epidermal growth factor receptor (EGFR) are initially responsive to EGFR tyrosine kinase inhibitors (EGFR-TKIs); however, they invariably develop resistance to these drugs. E7820 is an angiogenesis inhibitor that decreases integrin-α2 expression and is currently undergoing clinical trials. We investigated whether E7820 in combination with erlotinib, an EGFR-TKI, could overcome EGFR-TKI-resistance in the NSCLC cell lines A549 (KRAS; G12S), H1975 (EGFR; L858R/T790M), and H1650 (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 CD31 and TUNEL staining, respectively. Treatment with E7820 (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 HUVECs through activation of both intrinsic and extrinsic apoptosis pathways in vitro. The combination of E7820 with erlotinib is an alternative strategy to overcome erlotinib resistance in NSCLC by enhancement of the anti-angiogenic activity of E7820.

• Authors: Ken Ito, Taro Semba, Toshimitsu Uenaka, Toshiaki Wakabayashi, Makoto Asada, Yasuhiro Funahashi
• Journal: Cancer science (Cancer Sci) Vol. 105 Issue 8 Pg. 1023-31 (Aug 2014) ISSN: 1349-7006 [Electronic] England
• PMID: 24841832 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2014 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.

Chemical References

• Indoles
• Quinazolines
• Sulfonamides
• N-(3-cyano-4-methyl-1H-indol-7-yl)-3-cyanobenzene-sulfonamide
• Erlotinib Hydrochloride

Topics

• Animals
• Antineoplastic Combined Chemotherapy Protocols (pharmacology)
• Apoptosis (drug effects)
• Carcinoma, Non-Small-Cell Lung (pathology)
• Cell Line, Tumor
• Disease Models, Animal
• Drug Resistance, Neoplasm (drug effects)
• Erlotinib Hydrochloride
• Humans
• Immunohistochemistry
• In Situ Nick-End Labeling
• Indoles (administration & dosage)
• Lung Neoplasms (pathology)
• Mice
• Mice, Nude
• Quinazolines (administration & dosage)
• Sulfonamides (administration & dosage)
• Xenograft Model Antitumor Assays