Abstract
Abstract Colorectal carcinoma is the most common cancer worldwide. Cetuximab is the first-line target drug for late-stage metastatic colon cancer treatment; however, resistance to it was found in 45% patients having KRAS mutation. Therefore, the alternative signal axis to target mutated cancer cells is urgent and investigated. The role and the importance of Src has emerged in colon cancer; this study is to investigate the drug combined efficacy of cetuximab and dasatinib, the Src inhibitor and the underling molecular mechanism in KRAS/BRAF mutated cells. In this study, KRAS and BRAF mutated colon cancer cell lines SW480 and HT-29 were treated with cetuximab, dasatinib and fluorouracil (5-FU) solitary or combined. Cell viability and migration ability were monitored, and the molecular mechanisms were analyzed by Western blot for signal protein expressions. The in vivo study was carried with subcutaneous xenograft mouse model to evaluate the drug efficacy. The result showed that cetuximab treatment induced Src activation dose dependently, and induced matrix-dependent cell migration in SW480 cells. Cetuximab, dasatinib and 5-FU combined treatment compared to solitary treatment can reduce cell viability in either wild-type or KRAS/BRAF mutated colon cells. In the signal protein expressions, Src expression was suppressed sufficiently with dasatinib treatment; the phosphorylation of MAPK in SW480 cells and the phosphorylation of PI3K in HT-29 cells were downregulated after treated with cetuximab together with dasatinib and 5-FU. The drug combination was also demonstrated to suppress subcutaneous tumor growth as well. These findings demonstrate the combination of cetuximab, dasatinib and 5-FU can be the potential treating strategy for colon cancer cells with KRAS/BRAF mutation. Citation Format: Hsiang-Ling Chiu, Yi-Che Wu, Wan-Chen Wei, Ling-Yi Kao, Wei-Ting Chao. Cetuximab combined with dasatinib reduces drug resistance in KRAS/BRAF mutated colorectal carcinoma cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4035.
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