A PROTAC peptide induces durable β-catenin degradation and suppresses Wnt-dependent intestinal cancer

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Aberrant Wnt/β-catenin signaling is implicated in numerous cancers.
• β-catenin is a crucial intracellular target for cancer therapeutics.
• Previous studies utilized Axin-derived peptides to modulate Wnt/β-catenin signaling.

Purpose of the Study:

• To design and evaluate novel proteolysis targeting chimeras (PROTACs) for targeted β-catenin degradation.
• To assess the efficacy of xStAx-VHLL in inhibiting Wnt signaling and cancer progression.
• To explore the therapeutic potential of β-catenin degrader PROTACs in preclinical cancer models.

Main Methods:

• Design of PROTACs by conjugating β-catenin binding peptides (SAHPA1, xStAx) with VHL ligands.
• Evaluation of β-catenin degradation and Wnt signaling inhibition in cancer cells and APC organoids.
• Assessment of tumor growth inhibition in BALB/C nude mice and established tumors in APC mice.
• Testing the efficacy against colorectal cancer patient-derived organoids.

Main Results:

• The xStAx-VHLL PROTAC achieved sustained β-catenin degradation and potent Wnt signaling inhibition.
• xStAx-VHLL demonstrated significant tumor formation restraint and regression of existing tumors in vivo.
• The PROTAC effectively inhibited the survival of colorectal cancer patient-derived organoids.

Conclusions:

• xStAx-VHLL PROTACs are effective in degrading β-catenin and inhibiting Wnt signaling.
• These findings highlight the potential of β-catenin degrader PROTACs as a promising new class of anticancer agents.
• xStAx-VHLL shows significant promise for cancer prevention and treatment.