Abstract C43: Dasatinib resensitizes Kras mutant colorectal tumors to cetuximab

Abstract

Abstract Several recent clinical trials have demonstrated a strong correlation between Kras mutational status and resistance to cetuximab in metastatic colorectal cancer (mCRC). The work presented here sought to further understand the resistance of Kras mutant tumors to cetuximab and analyze dasatinib, a potent FDA approved SRC family kinase inhibitor, and its ability to overcome cetuximab resistance in this genetic setting. We analyzed 16 CRC lines for cetuximab growth response in vivo, expression of EGFR, SRC, and Kras mutational status. From this analysis we selected three Kras mutant lines (HCT116, LS180, LoVo), one Kras wild type line (SW48), and one EGFR negative line (Colo320DM) for further studies. Approximately two million cells from each line were inoculated in the dorsal flanks of athymic nude mice and allowed to grow to 100mm cubed. At that time mice were given 0.3mg of cetuximab twice weekly for 2 to 4 weeks. All Kras mutant lines were resistant to cetuximab in vivo, whereas the Kras wild type line showed significant tumor growth inhibition to cetuximab therapy. Each Kras mutant line was then analyzed for response to dasatinib alone. Mice were given 30mg/kg of dasatinib fives times weekly by oral gavage for 2 to 4 weeks. Results of these experiments indicated that Kras mutant tumors exhibited very little response to dasatinib monotherapy. However, dasatinib given in combination with cetuximab lead to significant tumor growth delay relative to vehicle controls. Collectively, these data suggest that Src and its family of kinases cooperate with the EGFR in the Kras mutant, mCRC setting and dual blockade has a distinct anti-tumor effect. These studies strengthen the rationale for the design of clinical trials combining dasatinib and cetuximab in the Kras mutant mCRC setting. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C43.