Exploring novel sensitizers Advancing BH3 mimetic efficacy in colorectal cancer therapeutics

The treatment of progressive colorectal cancers (CRC) still constitutes a great challenge due to their poor responsiveness to conventional therapies. Upregulation of anti-apoptotic BCL-2 family, particularly BCL-XL, is reported to endow CRC cells with resistance to apoptosis, which largely account for their low sensitivity to therapies. Thus, the BCL-2 family inhibitors, also termed as BH3 mimetics, exhibit potentials in CRC treatment, which still needs to be validated. In this study, we established a flow cytometry based method to specifically assess the apoptosis induction in cancer stem cell population. Consequently, this made it possible to extensively examine the sensitivity of CRC to BH3 mimetics. It was indicated that the combination of BCL-XL and MCL1 inhibitors displayed the highest potency in killing CRC. Nevertheless, due to its platelet toxicity, the application of BH3 mimetics has been restrained and need to be improved. Therefore, sensitizers to BH3 mimetics have been identified and the mechanisms of sensitization have been revealed. We identified two groups of compounds, effectively sensitizing CRC to low doses of BCL-XL inhibitors. Manidipine-2HCl, one of the potent sensitizer, was found to target UGT8 and reduce the sulfatides synthesis, which induced mitochondrial stress and facilitated BAX aggregation. Another group of agents targeting GSK3b, also synergized with BCL-XL inhibitors to mitigate the competitive advantage of APC mutant tumor cells. In this thesis, the efficacy of BH3 mimetics in CRC treatment was validated, providing a rationale for further investigation of BH3 mimetics based therapies in CRC treatment.