Targeted disruption of the BCL9/β-catenin complex inhibits oncogenic Wnt signaling

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• Aberrant Wnt/β-catenin signaling is a key driver in numerous human cancers.
• Targeting this pathway is challenging due to large protein interfaces and essential homeostatic roles.

Purpose of the Study:

• To develop a therapeutic strategy targeting the interaction between β-catenin and its co-activator B cell lymphoma 9 (BCL9).
• To investigate the anti-cancer effects of a novel agent designed to inhibit this interaction.

Main Methods:

• Development of a stabilized α helix of BCL9 (SAH-BCL9) to block β-catenin binding.
• Assessment of SAH-BCL9's ability to disrupt β-catenin/BCL9 complexes and suppress Wnt transcription.
• Evaluation of SAH-BCL9's anti-tumor effects in mouse xenograft models (Colo320 colorectal carcinoma, INA-6 multiple myeloma).

Main Results:

• SAH-BCL9 effectively targets β-catenin and dissociates native β-catenin/BCL9 complexes.
• SAH-BCL9 selectively suppresses oncogenic Wnt transcription.
• SAH-BCL9 demonstrated mechanism-based anti-tumor effects, inhibiting tumor growth, angiogenesis, invasion, and metastasis in preclinical models.

Conclusions:

• SAH-BCL9 represents a promising therapeutic prototype for cancers driven by deregulated Wnt signaling.
• Inhibiting the BCL9-β-catenin interaction offers a selective approach to suppress oncogenic Wnt transcription.