2. Academic Validation
  3. A novel β-catenin/BCL9 complex inhibitor blocks oncogenic Wnt signaling and disrupts cholesterol homeostasis in colorectal cancer

A novel β-catenin/BCL9 complex inhibitor blocks oncogenic Wnt signaling and disrupts cholesterol homeostasis in colorectal cancer

  • Sci Adv. 2022 Apr 29;8(17):eabm3108. doi: 10.1126/sciadv.abm3108.
Helen Tanton 1,  Tomasz Sewastianik 1 2,  Hyuk-Soo Seo 3 4,  David Remillard 5,  Roodolph St Pierre 5,  Pratyusha Bala 5 6,  Daulet Aitymbayev 5 6,  Peter Dennis 1,  Keith Adler 1,  Ezekiel Geffken 3,  Zoe Yeoh 3,  Nicholas Vangos 3,  Filip Garbicz 1 2,  David Scott 3,  Nilay Sethi 5 6 7 8,  James Bradner 5,  Sirano Dhe-Paganon 3 4,  Ruben D Carrasco 1 9
Affiliations

Affiliations

  • 1 Department of Oncologic Pathology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
  • 2 Department of Experimental Hematology, Institute of Hematology and Transfusion Medicine,, Warsaw, Poland.
  • 3 Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
  • 4 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA.
  • 5 Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
  • 6 Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA, USA.
  • 7 Gastrointestinal Cancer Center, Dana-Farber Cancer Institute, Boston, MA, USA.
  • 8 Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
  • 9 Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
PMID: 35486727 DOI: 10.1126/sciadv.abm3108
Abstract

Dysregulated Wnt/β-catenin signaling is implicated in the pathogenesis of many human cancers, including colorectal Cancer (CRC), making it an attractive clinical target. With the aim of inhibiting oncogenic Wnt activity, we developed a high-throughput screening AlphaScreen assay to identify selective small-molecule inhibitors of the interaction between β-catenin and its coactivator BCL9. We identified a compound that consistently bound to β-catenin and specifically inhibited in vivo native β-catenin/BCL9 complex formation in CRC cell lines. This compound inhibited Wnt activity, down-regulated expression of the Wnt/β-catenin signature in gene expression studies, disrupted Cholesterol homeostasis, and significantly reduced the proliferation of CRC cell lines and tumor growth in a xenograft mouse model of CRC. This study has therefore identified a specific small-molecule inhibitor of oncogenic Wnt signaling, which may have value as a probe for functional studies and has important implications for the development of novel therapies in patients with CRC.

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