B08

Mechanism of AXIN1 degradation after MEK inhibition

Funding period: 2021-2025

Project B08

Project Leaders

Dr. med. Tianzuo Zhan

Project Leader B08

Abstract

Small molecule inhibitors of MEK1/2 are clinically used for the treatment of cancers with activating Ras pathway mutations. Recently, MEK inhibitors were found to induce Wnt signaling in colorectal cancer, which is mediated by a rapid loss of AXIN1. AXIN1 is a main regulatory element of the destruction complex and its protein levels determine the activity of the canonical Wnt pathway. In this project, we will investigate if MEK inhibitors induce post-translational modifications of AXIN1, focusing on changes in phosphorylation and ubiquitination. We will determine if rewiring of interaction partners of AXIN1 occurs upon MEK inhibition and identify genetic alterations that modify the kinetics of AXIN1 degradation upon targeting of the Ras pathway.

Project-related Publications

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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