The human EGFR family consists of four type-1 transmembrane
tyrosine kinase receptors: HER1 (EGFR, ErbB1), HER2 (Neu, ErbB2), HER3 (ErbB3), and HER4 (ErbB4). HER3 can dimerize with EGFR, HER2 and even c-Met and likely plays a central role in the response to EGFR-targeted
therapy. Because HER3 lacks significant
kinase activity and cannot be inhibited by
tyrosine kinase inhibitors,
neutralizing antibodies and alternative inhibitors of HER3 have been sought as
cancer therapeutics. Here, we describe the stable suppression of HER3
mRNA and
protein using
siRNA. The inhibition of HER3 expression decreased cell proliferation, suppressed cell cycle progression, induced apoptosis and inhibited cell motility, migration, invasiveness, and soft
agar growth. In addition, we found that
gefitinib treatment increased the HER3 and HER2
mRNA levels. The administration of various concentrations of
gefitinib to HER3-knockdown cells enhanced antitumour activity and sensitivity due to the downregulation of
protein phosphorylation via PI3K/AKT and ERK signalling. Our results support the use of combined treatments targeting multiple EGFR receptors, particularly the use of HER3 inhibitors combined with EGFR inhibitors, such as
gefitinib.