Abstract
The inhibition of epidermal growth factor receptor (EGFR) signaling by Gefitinib provides a promising treatment strategy for non-small cell lung cancer (NSCLC); however, drug resistance to Gefitinib and other tyrosine kinase inhibitors presents a major issue. Using NSCLC cell lines with differential EGFR status, we examined the potency of PA-MSHA (Pseudomonas aeruginosa-mannose-sensitive hemagglutinin) in combination with Gefitinib on proliferation, apoptosis, cell cycle arrest, EGFR signaling and tumor growth. PC-9, A549, and NCI-H1975 cells were treated with PA-MSHA, Gefetinib, or PA-MSHA plus Gefetinib at different concentrations and times. The effects of the drugs on proliferation, cell cycle distribution and apoptosis were evaluated. The activation of EGFR and apoptotic signaling-related molecules was evaluated by Western blotting in the presence or absence of EGFR siRNA. Tumor growth and pathway signaling activation was assessed by xenografts in nude mice. A time-dependent and concentration-dependent cytotoxic effect of PA-MSHA was observed in all NSCLC cells tested. The combination of PA-MSHA plus Gefitinib enhanced the growth inhibition, sub-G1 content and apoptosis over that observed with either agent alone. Furthermore, the combination of PA-MSHA plus Gefitinib resulted in caspase-3/caspase-9 cleavage and increased inhibition of EGFR-dependent activation of AKT and ERK phosphorylation. Combination treatment was more effective in reducing tumor size and EGFR activation than either agent alone. These data suggest that PA-MSHA and Gefitinib function additively to suppress the proliferative effects of NSCLC cells of differential EGFR status. The combination of PA-MSHA and Gefitinib provides a potential new strategy to conquer drug resistance for anti-EGFR-targeted therapy of NSCLC.
Highlights
Lung cancer was one of the most common cancers for men and women in 2012 and the most common cause of cancer-related death
Using non-small cell lung cancer (NSCLC) cell lines with differential epidermal growth factor receptor (EGFR) status, we examined the potency of PA-MSHA (Pseudomonas aeruginosa-mannose-sensitive hemagglutinin) in combination with Gefitinib on proliferation, apoptosis, cell cycle arrest, EGFR signaling and tumor growth
To investigate the effect of PA-MSHA alone and in combination with Gefitinib, we examined three human NSCLC cell lines with varying genetic EGFR status and differential corresponding sensitivity to EGFRTKIs: PC-9, A549, and NCI-H1975
Summary
Lung cancer was one of the most common cancers for men and women in 2012 and the most common cause of cancer-related death. Second-generation EGFR TKIs that inhibit EGFR activity by irreversibly binding to EGFR have been clinically developed and have shown promising anti-tumor activity in NSCLC [8]. These irreversible EGFR TKIs are over 100-fold less potent in NSCLC cells with the EGFR T790M mutation than in NSCLC cells with the EGFR exon 19 in-frame deletion mutation [9, 10]. A recent clinical study emphasized the limited effects of these second-generation agents, which suggests the necessity for developing a new strategy for overcoming EGFR TKIs resistance in NSCLC [11]
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