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.

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.

• Authors: Xiao-Fang Guo, Xiao-Fei Zhu, Hai-Ying Cao, Gen-Shen Zhong, Liang Li, Bao-Guo Deng, Ping Chen, Pei-Zhen Wang, Qing-Fang Miao, Yong-Su Zhen
• Journal: Oncotarget (Oncotarget) Vol. 8 Issue 16 Pg. 27286-27299 (Apr 18 2017) ISSN: 1949-2553 [Electronic] United States
• PMID: 28460483 (Publication Type: Journal Article)

Chemical References

• Enediynes
• Recombinant Fusion Proteins
• Insulin-Like Growth Factor I
• ErbB Receptors

Topics

• Animals
• Apoptosis (drug effects)
• Carcinoma, Non-Small-Cell Lung (drug therapy, metabolism, pathology)
• Cell Cycle (drug effects)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Disease Models, Animal
• Enediynes (chemistry)
• ErbB Receptors (antagonists & inhibitors, metabolism)
• Female
• Humans
• Insulin-Like Growth Factor I (antagonists & inhibitors, metabolism)
• Lung Neoplasms (drug therapy, metabolism, pathology)
• Mice
• Protein Binding
• Recombinant Fusion Proteins (chemistry, metabolism, pharmacology)
• Signal Transduction (drug effects)
• Xenograft Model Antitumor Assays