A selective TNKS2 inhibitor for tumor-restricted WNT suppression
Hyperactive WNT signaling is a potent cancer driver, but clinical translation of WNT inhibitors has been hampered by on-target toxicities. WNT signaling can be constrained through inhibition of the PARP family enzymes Tankyrase 1 (TNKS1) and Tankyrase 2 (TNKS2), however, existing TNKS inhibitors suppress WNT signaling in both tumor and healthy tissues. In this study, we show that the loss of chromosome 8p that occurs in approximately half of advanced epithelial malignancies, creates a collateral vulnerability that enables tumor-selective inhibition of Tankyrase activity. 8p loss depletes expression of TNKS1 and creates a tumor-specific dependency on the functionally redundant TNKS2 protein. Through structure-guided drug design, we identify a first-in-class TNKS2-selective inhibitor that can drive selective WNT inhibition in TNKS1-deficient oncogenic cell and organoid models. This work demonstrates a targetable vulnerability in multiple cancer types, providing a new approach to potent and selective WNT-targeted therapies.
Authors
- David J. Huggins (ORCID: https://orcid.org/0000-0003-1579-2496)
- Efrat Finkin-Groner (ORCID: https://orcid.org/0000-0002-1458-7098)
- Lukas E. Dow (ORCID: https://orcid.org/0000-0001-7048-1418)
- Florencia P. Madorsky Rowdo (ORCID: https://orcid.org/0000-0002-8504-1690)
- Benjamin Hopkins (ORCID: https://orcid.org/0000-0003-1923-0239)
- Richard K. Hite (ORCID: https://orcid.org/0000-0003-0496-0669)
- John D. Ginn
- 孙姗
- Emma M. Schatoff (ORCID: https://orcid.org/0000-0002-7327-1843)
- Nigel J. Liverton (ORCID: https://orcid.org/0000-0002-3259-4558)
- Alyna Katti (ORCID: https://orcid.org/0000-0002-9662-965X)
- Kevan Chu (ORCID: https://orcid.org/0009-0009-5151-3096)
- Jill Zimmerman
- Yoshiyuki Fukase (ORCID: https://orcid.org/0000-0001-8088-2522)
- Brandon Malone (ORCID: https://orcid.org/0000-0001-7752-9824)
- Miguel Foronda (ORCID: https://orcid.org/0000-0001-9590-9281)
- Sukanya Goswami (ORCID: https://orcid.org/0009-0001-5598-3337)
- Elizabeth Granowsky
- Sher Bahadur (ORCID: https://orcid.org/0009-0007-6362-4151)
- Benjamin Leach
- Tanweer Khan
- Tuomas Tammela
- Heather Alcorn
- Rui Liang
Institutions
- Memorial Sloan Kettering Cancer Center (US)
- Tri-Institutional Therapeutics Discovery Institute (US)
- Weill Cornell Medicine (US)
- Weill Cornell Medical Center (US)
Publication Details
- Journal
- Nature Chemical Biology
- Published
- 2026-11-02
- DOI
- https://doi.org/10.1038/s41589-026-02358-z
- Citations
- 1
- Primary Topic
- Wnt/β-catenin signaling in development and cancer
- Type
- article
- Field-Weighted Citation Impact
- 1.72
Funders
- Memorial Sloan-Kettering Cancer Center
- Emerald Foundation
- National Institutes of Health
- Weill Cornell Medical College
- National Cancer Institute
- Division of Cancer Epidemiology and Genetics, National Cancer Institute