The proteasome plays a pivotal role in the turnover of regulatory transduction 
proteins induced by activated cell membrane growth factor receptors. The 
epidermal growth factor receptor (EGFR) pathway is crucial in the development 
and progression of human epithelial cancers. Proteasome inhibition may sensitize 
human cancer cell lines to EGFR inhibitors. We investigated the growth 
inhibitory and pro-apoptotic effects of the proteasome inhibitor bortezomib in 
combination with anti-EGFR drugs, such as gefitinib, vandetanib, and cetuximab 
in EGFR-expressing human cancer cell lines. Bortezomib determined dose-dependent 
growth inhibition in a nine cancer cell line panel (IC(50) values, range 6-42 
nM). A significant synergistic growth inhibitory effect was observed with the 
combination of bortezomib and each EGFR inhibitor in all cell lines (combination 
index, CI, range 0.10-0.55), which was accompanied by a significant induction in 
apoptosis by the combined treatment with bortezomib, cetuximab and vandetanib. 
In HCT-116 colon cancer and A549 lung adenocarcinoma cells, bortezomib plus EGFR 
inhibitor treatment induced a more effective inhibition of EGFR-activated 
down-stream signals, including a marked suppression in activated, phosphorylated 
Akt (P-Akt). In contrast, overexpression of a constitutively active P-Akt 
protected A549 cells by cell growth inhibition and apoptosis following treatment 
with bortezomib and EGFR inhibitors. The combined treatment with bortezomib and 
EGFR inhibitors has a synergistic growth inhibitory and pro-apoptotic activity 
in different human cancer cells which possess a functional EGFR-dependent 
autocrine growth pathway through to a more efficient and sustained inhibition of 
Akt.