Abstract C47: Dual kinase inhibition of EGFR and HER2 can overcome resistance to an EGFR-targeting agent

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Abstract EGFR and HER2 expression are correlated with poor prognosis in several cancers including bladder cancer. The EGFR-targeting agent cetuximab is currently in phase II clinical trials for the treatment of bladder cancer, but has only been modestly effective as a single agent in most solid tumor types. In colon cancer, lack of cetuximab efficacy has been attributed to compensatory activating mutations in Kras. The incidence of Kras mutations is rare in bladder carcinomas. There is a need for preclinical models with which to study resistance to EGFR-targeting agents. Here, we generated four cetuximab-resistant clones of a cetuximab-sensitive transitional bladder cancer cell line in vivo by exposing cetuximab-sensitive bladder cancer cell line xenografts to slowly increasing concentrations of cetuximab. We verified this resistance in vivo by demonstrating growth of cetuximab-resistant xenografts in the presence of high doses of cetuximab, as well as establishing differential sensitivity to cetuximab between sensitive and resistant xenografts in vivo. We validated the cetuximab-resistant phenotype of these cells in vitro by showing decreased response to cetuximab in an invasion assay. We examined the levels of total and phosphorylated EGFR, HER2, HER3, AKT, MAPK, and the total protein levels of epithelial-to-mesenchymal transition markers E-cadherin and Vimentin in the isogenic cetuximab-sensitive and cetuximab-resistant cells. Increased phosphorylation of the ERBB family members HER2 and HER3 was detected in cetuximab-resistant clones compared with their cetuximab-sensitive parental cell lines. Treatment of the cetuximab-resistant cells with an irreversible dual kinase inhibitor targeting EGFR and HER2 (BIBW2992), successfully inhibited their growth. These data suggest that activation of HER2 and HER3 may contribute to cetuximab resistance where targeting these other HER family members may enhance the efficacy of EGFR blockade. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C47.