A Small Molecule Inhibitor of the β-Catenin-TCF4 Interaction Suppresses Colorectal Cancer Growth In Vitro and In Vivo

Seung Ho Shin, Do Young Lim, Kanamata Reddy, Margarita Malakhova, Fangfang Liu, Ting Wang, Mengqiu Song, Hanyong Chen, Ki Beom Bae, Joohyun Ryu, Kangdong Liu, Mee Hyun Lee, Ann M. Bode, Zigang Dong

Research output: Contribution to journalArticle

16 Scopus citations

Abstract

Colorectal cancer is associated with aberrant activation of the Wnt pathway. β-Catenin plays essential roles in the Wnt pathway by interacting with T-cell factor 4 (TCF4) to transcribe oncogenes. We synthesized a small molecule, referred to as HI-B1, and evaluated signaling changes and biological consequences induced by the compound. HI-B1 inhibited β-catenin/TCF4 luciferase activity and preferentially caused apoptosis of cancer cells in which the survival is dependent on β-catenin. The formation of the β-catenin/TCF4 complex was disrupted by HI-B1 due to the direct interaction of HI-B1 with β-catenin. Colon cancer patient-derived xenograft (PDX) studies showed that a tumor with higher levels of β-catenin expression was more sensitive to HI-B1 treatment, compared to a tumor with lower expression levels of β-catenin. The different sensitivities of PDX tumors to HI-B1 were dependent on the β-catenin expression level and potentially could be further exploited for biomarker development and therapeutic applications against colon cancer.

Original languageEnglish (US)
Pages (from-to)22-31
Number of pages10
JournalEBioMedicine
Volume25
DOIs
StatePublished - Nov 2017

Keywords

  • Colorectal cancer
  • HI-B1
  • Patient-derived xenograft
  • Precision medicine
  • Small molecule inhibitor
  • β-catenin

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