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.
Highlights
Lung cancer has been the leading cause of cancer death worldwide
Another bispecific fusion protein EGF-LDP-Insulin-like growth factor (IGF) that differed in the location of the ldp from EGF-IGF-LDP was constructed for comparison
The results demonstrated that phosphoEGFR reduced significantly in the EGF-LDP-active enediyne chromophore (AE), LDPIGF-AE and EGF-IGF-LDP-AE treated tumors when compared with control group
Summary
Lung cancer has been the leading cause of cancer death worldwide. Non-small cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancers, with this encompassing the pathologically distinct adenocarcinoma, squamous cell carcinoma, and large cell carcinoma types. EGFR, a member of ErbB receptor tyrosine kinase family, is known to play important roles in promoting cell survival, proliferation, differentiation, migration and angiogenesis when activated by ligand (EGF, TGF-α, etc) binding [4]. Therapeutic strategies targeting IGF-1R, including the use of mAbs, TKIs, and IGF ligand neutralizing antibodies have been explored in preclinical studies. They inhibited the growth of IGF-IR expressing tumor cells in vitro and in vivo, and enhance responses of cancer cells to treatments with cytotoxic drugs or radiotherapy [18,19,20,21,22,23,24,25]
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