Targeting EGFR and ErbB2 by small molecule tyrosine kinase inhibitors in human colon cancer
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With the understanding of the molecular pathogenesis of colorectal cancer, novel molecular targeted therapies are being developed that may improve treatment of colorectal cancer. The identification of a causal role of deregulated EGFR signaling in tumorigenesis and progression of colorectal cancer provides the rationale to target this proto-oncogene as a potential treatment. However, despite the fact that up to 80% colorectal cancers appear to utilize EGFR for tumor growth, single agent anti-EGFR monoclonal antibodies achieved at best a 10% response rate and no EGFR tyrosine kinase inhibitors (TKIs) have shown activity in this disease so far. The hypothesis of this study is that aberrant ErbB2 signaling may provide for a potential drug resistance mechanism to EGFR single TKIs. Therefore, targeting both EGFR and ErbB2 kinase simultaneously by small molecule TKIs could achieve superior efficacy than single EGFR TKIs in colorectal cancer. This study examined this hypothesis using a combinational approach for EGFR and ErbB2 TKIs in two human colorectal carcinoma cell models, FET6αS26X and GEO. Both cell lines express multiple ErbB receptors, but not ErbB4, and harbor a deregulation of ErbB autocrine loop of TGFα/EGFR and/or heregulin/ErbB3. A synergistic effect of inhibition on tumor cell proliferation was achieved by a combination of EGFR and ErbB2 TKIs, AG1478 and AG879, in both cell models. Furthermore, the synergy of inhibition on cell proliferation was associated with apoptosis induction in both cell models, arguing for a general benefit of combination in colorectal cancer cells expressing multiple ErbB receptors. Exploration of the mechanisms of synergy revealed that combination treatment sufficiently blocked both EGFR and ErbB2 activation arising from heterodimerization. Downstream signaling mediated through ErbB receptors, including MAPK, AKT and PLC-γ pathways, are suppressed by the combination treatment as well. The novel dual EGFR and ErbB2 TKI, GW572016 was shown to have a superior efficacy to single ErbB TKIs and an equivalent efficacy as the combination approach in both cell models. The in vitro efficacy of GW572016 was translated into tumor xenograft studies demonstrating the anti-tumor effect of this compound. In summary, our data support the investigation of the dual EGFR and ErbB2 TKI GW572016 for colorectal cancer treatment.