LAUSR

5-Fluorouracil (5-FU) is a cytotoxic anticancer drug commonly used for patients with advanced colon cancer. This drug effectively reduces the size of tumors to a certain degree; however, cancer cells can gradually acquire resistance, resulting in disease progression. To identify the mechanism of 5-FU resistance, we established three 5-FU-resistant colon cancer cell lines and analyzed both apoptosis-related protein expression levels and BH3 profiling. These 5-FU-resistant colon cancer cell lines acquired apoptotic resistance to 5-FU. Although apoptosis-related protein expression levels were altered in each 5-FU-resistant colon cancer cell line variably, BH3 profiling indicated BCLXL dependence in 5-FU-resistant HT-29 cells only. Functional BCLXL inhibition in 5-FU-resistant HT-29 cells not only sensitized the cells to apoptosis but also overcame 5-FU resistance. The apoptotic BIM protein was preferentially sequestered, thereby resulting in acquired dependence on BCLXL for survival. Additionally, in vivo models showed that BCLXL inhibition controlled tumor progression. These results indicate that BH3 profiling facilitates the identification of the functional role of anti-apoptotic proteins during drug resistance and has clinical implications for colon cancer in targeting specific proteins such as BCLXL.