Clinical efficacy of
gefitinib (
ZD1839,
Iressa), which is an inhibitor specific for
epidermal growth factor (
EGF) receptor tyrosine kinase, has been shown in
non-small-cell lung carcinoma patients with
EGF receptor mutations, so these mutations are useful marker(s) to find a responder for the drug. Recent studies have shown that the
EGF receptor gene mutation is rare in
squamous cell carcinoma in the esophageal and head and neck regions. We previously reported that the expression of the
chemokine BRAK/CXCL14 in
head and neck squamous cell carcinoma (
HNSCC) cells was down-regulated by
EGF treatment, and that forced expression of BRAK in
tumor cells decreased the tumorigenicity of the cells in xenografts. Thus, we investigated the relationship between restoration of BRAK expression by
gefitinib and the efficacy of the drug for
tumor suppression. We found that
EGF down-regulated BRAK expression through the
MEK-
extracellular signal regulated kinase pathway and that this down-regulated expression was restored by
gefitinib in vitro.
Oral administration of
gefitinib significantly (P < 0.001) reduced
tumor growth of xenografts of three
HNSCC cell lines (HSC-2, HSC-3, and HSC-4), in female athymic nude mice, accompanied by an increase in BRAK expression specifically in
tumor tissue. This
tumor-suppressing effect of the drug was not observed in the case of BRAK non-expressing cells. Furthermore introduction of BRAK
shRNA vector reduced both the expression levels of BRAK in HSC-3 cells and the antitumor efficacy of
gefitinib in vivo. Our data showing an inverse relationship between BRAK expression levels in
tumor cells and the
tumor growth rate indicate that the
gefitinib-induced increase in BRAK expression is beneficial for
tumor suppression in vivo.