Targeting tankyrase scaffolding in the β-catenin destruction complex by PROTAC overcomes the limitation of catalytic inhibitors in colorectal cancer
- 1Department of Biochemistry, UT Southwestern Medical Center, Dallas, United States
- 2Department of Cell Biology, UT Southwestern Medical Center, Dallas, United States
Abstract
Aberrant WNT/β-catenin signaling drives tumorigenesis and metastasis in cancer. Although enzymatic inhibitors of tankyrase (TNKS) effectively block AXIN degradation and stabilize the β-catenin destruction complex (DC), they have demonstrated limited efficacy in various colorectal cancer (CRC) models. Here, we demonstrate that, unexpectedly, the induction of AXIN puncta represents a major barrier to achieving therapeutic efficacy. Mechanistically, catalytic inhibition of TNKS prevents TNKS turnover and drives its accumulation in the DC, wherein the scaffolding function of TNKS induces AXIN puncta formation, rigidifies the DC, and impedes β-catenin turnover. Chemically induced degradation of TNKS overcomes this limitation by stabilizing AXIN without puncta formation, providing a deeper suppression of the WNT/β-catenin pathway activity and the proliferation of CRC cells harboring dysfunctional APC mutations. Collectively, these findings provide an explanation for the unsatisfactory outcomes of drugging the WNT/β-catenin signaling pathway by TNKS inhibitors and highlight TNKS degradation as a promising approach to treat WNT/β-catenin-driven CRC.
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BibTeX
@article{wang2026targeting,
title = {{Targeting tankyrase scaffolding in the β-catenin destruction complex by PROTAC overcomes the limitation of catalytic inhibitors in colorectal cancer}},
author = {Qian Wang and Liping Li and Lin You and Shuai Wang and Lei Han and Bingnan Wang and Liping Yao and Yesu Addepalli and Yong Lu and Ilgen Mender and Ann M Flusche and Chiho Kim and Nageswari Yarravarapu and Andrew Lemoff and Lawrence Lum and Jerry W Shay and Yonghao Yu and Chuo Chen},
journal = {eLife},
year = {2026},
month = nov,
doi = {10.7554/elife.109052},
url = {https://elifesciences.org/articles/109052},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Targeting tankyrase scaffolding in the β-catenin destruction complex by PROTAC overcomes the limitation of catalytic inhibitors in colorectal cancer
AU - Qian Wang
AU - Liping Li
AU - Lin You
AU - Shuai Wang
AU - Lei Han
AU - Bingnan Wang
AU - Liping Yao
AU - Yesu Addepalli
AU - Yong Lu
AU - Ilgen Mender
AU - Ann M Flusche
AU - Chiho Kim
AU - Nageswari Yarravarapu
AU - Andrew Lemoff
AU - Lawrence Lum
AU - Jerry W Shay
AU - Yonghao Yu
AU - Chuo Chen
PY - 2026
DA - 2026/11/04
JO - eLife
DO - 10.7554/elife.109052
UR - https://elifesciences.org/articles/109052
AB - Aberrant WNT/β-catenin signaling drives tumorigenesis and metastasis in cancer. Although enzymatic inhibitors of tankyrase (TNKS) effectively block AXIN degradation and stabilize the β-catenin destruction complex (DC), they have demonstrated limited efficacy in various colorectal cancer (CRC) models. Here, we demonstrate that, unexpectedly, the induction of AXIN puncta represents a major barrier to achieving therapeutic efficacy. Mechanistically, catalytic inhibition of TNKS prevents TNKS turnover and drives its accumulation in the DC, wherein the scaffolding function of TNKS induces AXIN puncta formation, rigidifies the DC, and impedes β-catenin turnover. Chemically induced degradation of TNKS overcomes this limitation by stabilizing AXIN without puncta formation, providing a deeper suppression of the WNT/β-catenin pathway activity and the proliferation of CRC cells harboring dysfunctional APC mutations. Collectively, these findings provide an explanation for the unsatisfactory outcomes of drugging the WNT/β-catenin signaling pathway by TNKS inhibitors and highlight TNKS degradation as a promising approach to treat WNT/β-catenin-driven CRC.
SN - 2050-084X
ER -