Targeting tankyrase scaffolding in the β-catenin destruction complex by PROTAC overcomes the limitation of catalytic inhibitors in colorectal cancer.

PROTAC-mediated degradation of tankyrase (TNKS) overcomes AXIN puncta–driven resistance that limits catalytic TNKS inhibitors, enabling deeper WNT/β-catenin suppression in colorectal cancer cells with dysfunctional APC mutations.

• Why it matters: Catalytic TNKS inhibitors can block AXIN degradation and stabilize the β-catenin destruction complex, yet show limited efficacy across colorectal cancer models, leaving a mechanistic barrier unexplained.
• What they did: The study shows that AXIN puncta induction is a major barrier: catalytic TNKS inhibition prevents TNKS turnover, accumulates TNKS in the destruction complex, and promotes puncta formation that rigidifies the complex and impedes β-catenin turnover; TNKS degradation via PROTAC stabilizes AXIN without puncta formation.
• The result: TNKS degradation provides deeper suppression of WNT/β-catenin pathway activity and reduces proliferation of CRC cells with dysfunctional APC mutations, supporting TNKS degradation as a promising therapeutic strategy.

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