B08

Mechanism of Wnt activation after KRAS inhibition

Funding period: 2021-2029

Project B08

Project Leaders

Prof. Dr. med. Tianzuo Zhan

 Project Leader B08

Abstract

The Wnt and Ras pathways are intricately connected in colorectal cancer, thereby supporting carcinogenesis and late-stage cancer phenotypes. We showed that MEK1/2 inhibition stimulates Wnt signaling in colorectal cancer models and uncovered AXIN1 loss by combined transcriptional and translational repression as a potential underlying mechanism. Here, we will extend our focus to pan-KRAS inhibition-mediated stimulation of Wnt signaling, and aim to identify common and differential mechanisms of activation in comparison to MEK1/2 inhibitors.

Project-related Publications

Combined MEK and PARP inhibition enhances radiation response in rectal cancer

Xiao Q, Riedesser JE, Mulholland T, Li Z, Buchloh J, Albrecht P, Yang X, Li M, Venkatachalam N, Skabkina O, Klupsch A, Eichhorn E, Wang L, Belle S, Schulte N, Schmitz D, Froelich MF, Trikhirhisthit K, Valentini E, Boonekamp KE, Petersen Y, Miersch T, Burgermeister E, Herskind C, Veldwijk MR, Brochhausen C, Ihnatko R, Krijgsveld J, Kurth I, Zhu Y, Ma Y, Cao K, Boutros M, Ebert MP, Zhan T, Betge J. Cell Rep Med. 2025 Aug 5:102284. doi: 10.1016/j.xcrm.2025.102284. Online ahead of print.

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Digestive cancers: mechanisms, therapeutics and management

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The Roles of Secreted Wnt Ligands in Cancer

Werner J, Boonekamp KE, Zhan T, Boutros M. Int J Mol Sci. 2023 Mar 10;24(6):5349. doi: 10.3390/ijms24065349. PMID: 36982422

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Cross-Talk between p53 and Wnt Signaling in Cancer

Xiao Q, Werner J, Venkatachalam N, Boonekamp KE, Ebert MP, Zhan T. Biomolecules. 2022 Mar 15;12(3):453. doi: 10.3390/biom12030453. PMID: 35327645

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Multi-omics integration identifies a selective vulnerability of colorectal cancer subtypes to YM155

Zhan T, Faehling V, Rauscher B, Betge J, Ebert MP, Boutros M. Int J Cancer. 2021 Apr 15;148(8):1948-1963. doi: 10.1002/ijc.33393. Epub 2020 Dec 4.
PMID: 33186476

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MEK inhibitors activate Wnt signalling and induce stem cell plasticity in colorectal cancer

Zhan T, Ambrosi G, Wandmacher AM, Rauscher B, Betge J, Rindtorff N, Häussler RS, Hinsenkamp I, Bamberg L, Hessling B, Müller-Decker K, Erdmann G, Burgermeister E, Ebert MP, Boutros M. Nat Commun. 2019 May 16;10(1):2197. doi: 10.1038/s41467-019-09898-0. PMID: 31097693

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CRISPR/Cas9 for cancer research and therapy

Zhan T, Rindtorff N, Betge J, Ebert MP, Boutros M. Semin Cancer Biol. 2019 Apr;55:106-119. doi: 10.1016/j.semcancer.2018.04.001. Epub 2018 Apr 16. PMID: 29673923

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Wnt signaling in cancer

Zhan T, Rindtorff N, Boutros M. Oncogene. 2017 Mar;36(11):1461-1473. doi: 10.1038/onc.2016.304. Epub 2016 Sep 12. PMID: 27617575

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CRISPRlibrary designer (CLD): software for multispecies design of single guide RNA libraries.

Heigwer F, Zhan T, Breinig M, Winter J, Brügemann D, Leible S, Boutros M. Genome Biol. 2016 Mar 24;17:55. doi: 10.1186/s13059-016-0915-2. PMID: 27013184

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