BET protein-dependent E2F pathway activity confers bell-shaped type resistance to tankyrase inhibitors in APC-mutated colorectal cancer

Cancer Lett. 2024 Mar 1:584:216632. doi: 10.1016/j.canlet.2024.216632. Epub 2024 Jan 11.

Abstract

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 suppressed 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.

Keywords: BET inhibitor; Colorectal cancer; Drug resistance; Tankyrase; WNT/β-catenin signaling.

MeSH terms

  • Adenomatous Polyposis Coli* / drug therapy
  • Animals
  • Antineoplastic Agents* / pharmacology
  • Antineoplastic Agents* / therapeutic use
  • Cell Line, Tumor
  • Colorectal Neoplasms* / drug therapy
  • Colorectal Neoplasms* / genetics
  • Colorectal Neoplasms* / pathology
  • Disease Models, Animal
  • Humans
  • Mice
  • Tankyrases*
  • Wnt Signaling Pathway
  • beta Catenin / metabolism

Substances

  • Antineoplastic Agents
  • beta Catenin
  • Tankyrases
  • TNKS protein, human
  • APC protein, human
  • DNER protein, human