Abstract 2057: Small molecule CB001 induces extrinsic apoptosis via downregulation of c-FLIP expression in mutant p53-expressing cancer cells

Abstract

Abstract Cellular FADD-like IL-1β-converting enzyme-inhibitory protein (c-FLIP) is a master anti-apoptotic regulator in cancer cells. c-FLIP inhibits caspase 8 activation and suppresses cell apoptosis induced by TNF-related apoptosis-inducing ligand (TRAIL) in malignant cells. Targeting c-FLIP is an attractive strategy for cancer therapy. We previously identified a small-molecule CB001 as a p53-restoring compound and found that CB001 induces cell death with little or no genotoxicity in human colorectal cancer cells. We now show that CB001 downregulates c-FLIP expression in cancer cells at the post-translational level via protein degradation. CB001 treatment induces an increase in caspase 8 activity which correlates with the decrease in c-FLIP at the protein level in mutant p53-expressing cancer cells. Knockdown of caspase 8 rescues cancer cells from CB001-induced apoptosis in mutant p53-expressing cancer cells, suggesting that downregulation of c-FLIP is one of the major mechanisms by which CB001 induces extrinsic cell apoptosis. Furthermore, our studies reveal a synergy between CB001 and TRAIL to induce apoptosis in TRAIL-resistant cancer cells, but not in normal cells at the tested doses. These results taken together suggest that CB001 is a promising lead for drug development with a strong capability to suppress tumor growth through targeting c-FLIP in cancer cells. Citation Format: Shengliang Zhang, Lanlan Zhou, Marie D. Ralff, Wafik S. El-Deiry. Small molecule CB001 induces extrinsic apoptosis via downregulation of c-FLIP expression in mutant p53-expressing cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2057.