BET protein-dependent E2F pathway activity confers bell-shaped type resistance to tankyrase inhibitors in APC-mutated colorectal cancer
- Cancer Lett. 2024 Jan 10:216632. doi: 10.1016/j.canlet.2024.216632.
- 1. Division of Molecular Biotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan; Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Chiba, Japan.
- 2. Division of Molecular Biotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan.
- 3. Drug Discovery Chemistry Platform Unit, RIKEN Center for Sustainable Resource Science, Wako, Saitama, Japan.
- 4. Department of Colorectal Surgery, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan; Department of Surgery, Uji-Tokushukai Medical Center, Kyoto, Japan.
- 5. Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Chiba, Japan; Division of Experimental Chemotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan.
- 6. Division of Molecular Biotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan; Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Chiba, Japan. Electronic address: [email protected].
Wnt/β-catenin signaling is aberrantly activated in colorectal Cancer (CRC) mainly by loss-of-function mutations in adenomatous polyposis coli (APC) and is involved in tumor progression. Tankyrase inhibitors, which suppress Wnt/β-catenin signaling, are currently in pre-clinical and clinical trials. However, the mechanisms of resistance to tankyrase inhibitors remain unclear. In this study, we established tankyrase inhibitor-resistant CRC cells, JC73-RK100, from APC-mutated patient-derived CRC cells. JC73-RK100 cells and several CRC cell lines were sensitive to tankyrase inhibitors at low concentrations but were resistant at high concentrations, showing an intrinsic/acquired bell-shaped dose response. Mechanistically, tankyrase inhibitors at high concentrations promoted BRD3/4-dependent E2F target gene transcription and over-activated cell cycle progression in these cells. BET inhibitors canceled the bell-shaped dose response to tankyrase inhibitors. Combination of tankyrase and BET inhibitors significantly suppress tumor growth in a mouse xenograft model. These observations suggest that the combination of tankyrase and BET inhibitors may be a useful therapeutic approach to overcome the resistance of a subset of CRCs to tankyrase inhibitors.