Chemoprevention of murine lung cancer by gefitinib in combination with prostacyclin synthase overexpression☆

Abstract 

Introduction

We hypothesized that the combination of the EGFR tyrosine kinase inhibitor (TKI) gefitinib with the powerful chemopreventive manipulation of lung-specific transgenic prostacyclin synthase (PGIS) overexpression on tumorigenesis in FVB/N mice would result in augmented chemoprevention.

Materials and methods

Wildtype and littermate PGIS overexpressors (OE) were given urethane, 1mg/kg i.p. followed by thrice weekly i.p. injections of gefitinib, 50mg/kg or 100mg/kg, or vehicle. Pulmonary adenomas were enumerated and measured.

Results

Gefitinib at either 50mg/kg or 100mg/kg administered i.p. three times weekly was effective in inhibiting EGF induced EGFR tyrosine phosphorylation and downstream signaling. The PGIS overexpressors showed significant decreases in tumor multiplicity consistent with prior studies. Gefitinib had no effect on tumor multiplicity or volume in wildtype mice. Among the PGIS overexpressors, a significant reduction in tumor multiplicity was shown in the 50mg/kg, but not the 100mg/kg, gefitinib treatment group vs. vehicle control animals (1.13±0.29 vs. 2.29±0.32 tumors/mouse, p=0.015). We examined the phosphorylation status in selected downstream effectors of EGFR (Erk, Akt, Src, PTEN). The major difference in the 50mg/kg vs. 100mg/kg group was an increase in p-Src in the PGIS OE mice receiving the higher dose.

Conclusion

We conclude that gefitinib alone has no chemopreventive efficacy in this model; it augmented the effect of PGIS overexpression at 50mg/kg but not 100mg/kg. Increased p-Src is correlated with loss of efficacy at the higher dose, suggesting the potential for combined EGFR and Src inhibition strategies in chemoprevention.

Keywords: Chemoprevention, Lung cancer, Transgenic mice, Src, EGFR, Gefitinib, Prostacyclin