Coexpression of the
epidermal growth factor receptor (EGFR) family receptors is found in a subset of
colon cancers, which may cooperatively promote
cancer cell growth and survival, as heterodimerization is known to provide for diversification of signal transduction. Recently, efforts have been made to develop novel
4-anilinoquinazoline and pyridopyrimidine derivatives to inhibit EGFR and ErbB2
kinases simultaneously. In this study, we tested the efficacy of a novel reversible dual inhibitor
GW572016 compared with the selective EGFR and ErbB2
tyrosine kinase inhibitors (TKI)
AG1478 and
AG879 and their combination, using the human
colon adenocarcinoma GEO mode. GEO cells depend on multiple
ErbB receptors for aberrant growth. A synergistic effect on inhibition of cell proliferation associated with induction of apoptosis was observed from the combination of
AG1478 and
AG879. Compared with
AG1478 or
AG879, the single TKI compound
GW572016 was a more potent inhibitor of GEO cell proliferation and was able to induce apoptosis at lower concentrations. Western blot analysis revealed that
AG1478 and
AG879 were unable to suppress both EGFR and ErbB2 activation as well as the downstream
mitogen-activated protein kinase (MAPK) and AKT pathways as single agents. In contrast,
GW572016 suppressed the activation of EGFR, ErbB2, MAPK, and AKT in a concentration-dependent manner. Finally, in vivo studies showed that
GW572016 treatment efficiently blocked GEO xenograft growth at a dose range of 30 to 200 mg/kg with a twice-daily schedule. In summary, our study indicates that targeting both EGFR and ErbB2 simultaneously could enhance
therapy over that of single agents directed at EGFR or ErbB2 in
cancers that can be identified as being primarily heterodimer-dependent.