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Oncotarget. 2017 Apr 18;8(16):27286-27299. doi: 10.18632/oncotarget.15933.

A bispecific enediyne-energized fusion protein targeting both epidermal growth factor receptor and insulin-like growth factor 1 receptor showing enhanced antitumor efficacy against non-small cell lung cancer.

Author information

1
Department of Microbiology, School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, China.
2
Department of Clinical Immunology, School of Laboratory Medicine, Xinxiang Medical University, Xinxiang, China.
3
Henan Collaborative Innovation Center of Molecular Diagnosis and Laboratory Medicine, Xinxiang, China.
4
Laboratory of Cancer Biotherapy, Institute of Neurology, The First Affiliated Hospital of Xinxiang Medical University, Weihui, China.
5
Department of Oncology, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Perking Union Medical College, Beijing, China.

Abstract

Epidermal growth factor receptor (EGFR) and insulin-like growth factor 1 receptor (IGF-1R) both overexpressed on non-small cell lung cancer (NSCLC) and are known cooperatively to promote tumor progression and drug resistance. This study was to construct a novel bispecific fusion protein EGF-IGF-LDP-AE consisting of EGFR and IGF-IR specific ligands (EGF and IGF-1) and lidamycin, an enediyne antibiotic with potent antitumor activity, and investigate its antitumor efficacy against NSCLC. Binding and internalization assays showed that EGF-IGF-LDP protein could bind to NSCLC cells with high affinity and then internalized into cells with higher efficiency than that of monospecific proteins. In vitro, the enediyne-energized analogue of bispecific fusion protein (EGF-IGF-LDP-AE) displayed extremely potent cytotoxicity to NSCLC cell lines with IC50<10-11 mol/L. Moreover, the bispecific protein EGF-IGF-LDP-AE was more cytotoxic than monospecific proteins (EGF-LDP-AE and LDP-IGF-AE) and lidamycin. In vivo, EGF-IGF-LDP-AE markedly inhibited the growth of A549 xenografts, and the efficacy was more potent than that of lidamycin and monospecific counterparts. EGF-IGF-LDP-AE caused significant cell cycle arrest and it also induced cell apoptosis in a dosage-dependent manner. Pretreatment with EGF-IGF-LDP-AE inhibited EGF-, IGF-stimulated EGFR and IGF-1R phosphorylation, and blocked two main downstream signaling molecules AKT and ERK activation. These data suggested that EGF-LDP-IGF-AE protein would be a promising targeted agent for NSCLC patients with EGFR and/or IGF-1R overexpression.

KEYWORDS:

EGFR; IGF-1R; NSCLC; bispecific fusion protein; lidamycin

PMID:
28460483
PMCID:
PMC5432335
DOI:
10.18632/oncotarget.15933
[Indexed for MEDLINE]
Free PMC Article

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