PURPOSE: Patients with recurrent prostate cancer are commonly treated with 
androgen withdrawal therapy (AWT); however, almost all patients eventually 
progress to castration resistant prostate cancer (CRPC), indicating failure of 
AWT to eliminate androgen-sensitive prostate cancer. The overall goal of these 
studies is to determine whether dual inhibition of the receptor tyrosine kinases 
epidermal growth factor receptor (EGFR) and HER2 would prolong the effectiveness 
of this treatment in prostate cancer.
EXPERIMENTAL DESIGN: We used androgen-dependent LNCaP cells and its CRPC 
sublines LNCaP-AI and C4-2. Additional data were collected in pRNS-1-1 cells 
stably expressing a mutant androgen receptor (AR-T877A), and in nude mice 
harboring CWR22 tumors. Studies utilized EGFR inhibitors erlotinib and AG1478, 
and HER2 inhibitors trastuzumab and AG879.
RESULTS: Dual EGFR/HER2 inhibition induced apoptosis selectively in 
androgen-sensitive prostate cancer cells undergoing AWT, but not in the presence 
of androgens, or in CRPC cells. We show that AWT alone failed to induce 
significant apoptosis in androgen-dependent cells, due to AWT-induced increase 
in HER2 and ErbB3, which promoted survival by increasing Akt phosphorylation. 
AWT-induced ErbB3 stabilized the AR and stimulated PSA, while it was inactivated 
only by inhibition of both its dimerization partners EGFR and HER2 (prostate 
cancer cells do not express ErbB4); but not the inhibition of any one receptor 
alone, explaining the success of dual EGFR/HER2 inhibition in sensitizing 
androgen-dependent cells to AWT. The effectiveness of the inhibitors in 
suppressing growth correlated with its ability to prevent Akt phosphorylation.
CONCLUSION: These studies indicate that dual EGFR/HER2 inhibition, administered 
together with AWT, sensitize prostate cancer cells to apoptosis during AWT.