Abstract A75: Dual inhibition of EGFR and ErbB2 during androgen ablation prevent the progression of prostate cancer cells to androgen independence

Abstract

Abstract Introduction: Patients with metastatic prostate cancer are treated with androgen ablation therapy which is initially effective, but most patients on this therapy ultimately become refractory to this treatment. Studies show that androgen withdrawal does not result in cell death, but simply cell growth arrest, whereas the development of androgen independence allows them to come out of the growth arrest and undergo cell cycle progression. Hence, induction of apoptosis during androgen ablation will prevent progression to androgen independence. The goal of the present project is to determine whether dual inhibition of EGFR and ErbB2 in prostate cancer cells during androgen withdrawal prevent their progression to androgen independence. EGFR, ErbB2, ErbB3 and ErbB4 constitute a family of receptor tyrosine kinases that require dimerization for complete activation. Experimental Procedures: Androgen dependent LNCaP prostate cancer cells and its androgen-independent subline LNCaP-AI were treated with combinations of the EGFR inhibitors AG1478 or Erlotinib (Tarceva), and the ErbB2 inhibitors AG879 or Trastuzumab (Herceptin), either in the presence of androgens, or together with androgen withdrawal. These experiments were also conducteds in androgen receptor (AR)-null pRNS-1-1 cells transfected with vector only, wild type AR or mutant AR(T877A). Results: Dual inhibition of EGFR and ErbB2 was more effective in inhibiting cell growth compared to single inhibition of either kinase. This effect was more pronounced in the absence of androgens compared to its presence, and was also more effective in androgen-dependent than in androgen-independent cells. Investigation of the mechanism of this effect demonstrated that dual inhibition of EGFR and ErbB2 also inhibited ErbB3 phosphorylation, likely by preventing its dimerization. Androgen withdrawal results in increased Akt phosphorylation, and we show here that dual EGFR/ErbB2 inhibition, but not single inhibition, prevented this effect and induced apoptosis. This effect is most pronounced in androgen sensitive cells undergoing androgen ablation, whereas in androgen-independent cells where Akt phosphorylation is already increased, the effect of the dual inhibition was less pronounced. Conclusions: Our results indicate that cell survival during androgen withdrawal caused by an increase in Akt phosphorylation may be prevented by dual use of EGFR and ErbB2 inhibitors. If the cells can be killed during androgen ablation, then no cells will remain to progress to androgen independence. Hence, the effect of the dual inhibition prevents the development of androgen-independence in prostate cancer cells. The significance of these results is that they suggest that the use of dual EGFR/ErbB2 inhibitors during androgen ablation may prevent the development of androgen independence in patients undergoing androgen ablation therapy. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A75.