Evaluation of Antitumor Potential of an Anti-Glypican-1 Monoclonal Antibody in Preclinical Lung Cancer Models Reveals a Distinct Mechanism of Action

Abstract Emerging evidence has revealed the distinct role of glypican-1 (GPC1) in mediating cellular signal transduction crucial to tumor progression through its function as a co-receptor/modulator for heparin-binding growth factors. The main objective of this study was to investigate the antitumor effect of a novel mouse anti-human GPC1 monoclonal antibody (anti-GPC1 mAb) on non-small cell lung carcinoma (NSCLC) and associated molecular mechanisms. Results of the in vitro study showed that anti-GPC1 mAb profoundly inhibited the anchorage-independent growth of A549 and H460 NSCLC cells and exhibited relatively high cytotoxic activities towards CCD-19Lu lung fibroblasts, A549/CCD-19Lu and H460/CCD-19Lu coculture spheroids. In the transwell indirect co-culture system, anti-GPC1 mAb treatment significantly decreased the expression of phospho-Src (Tyr416), phospho-Akt (Ser473) and β-catenin in the co-cultured CCD-19Lu lung fibroblasts, and the expression of phospho-MEK (Ser217/221) and phospho-p90RSK (Ser380) in co-cultured A549 cells. When anti-GPC1 mAb was administered to tumor-bearing mice either through tail-vein injection once every 72 hours for 8 doses or through intraperitoneal injection once a week for 3 doses and then once every 10 days for 2 more doses, the inhibitory effect of anti-GPC1 mAb on the growth of orthotopic A549 lung tumors was not statistically significant. Nonetheless, results of Western blot analysis showed significant decrease in the phosphorylation of FGFR1 at Tyr766, Src at Tyr416, ERK at Thr202/Tyr204, RSK at Ser380, GSK3α at Ser21 and GSK3β at Ser9 in tumor samples obtained from tumor-bearing mice receiving the extended-interval dosing of anti-GPC1 mAb. These data implicate that anti-GPC1 mAb treatment impairs the interaction between tumor cells and tumor associated fibroblasts by attenuating the paracrine FGFR signal transduction. In conclusion, although anti-GPC1 mAb alone is not sufficient to inhibit lung tumor growth in vivo, the relatively potent cytotoxicity of anti-GPC1 mAb in lung fibroblasts and its potential inhibitory effect on the paracrine FGFR signal transduction warrant further studies on the combined use of this mAb with targeted therapeutics to improve therapeutic outcomes in lung cancer.