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Kobelt D, Perez-Hernandez D, Fleuter C, et al. The newly identified MEK1 tyrosine phosphorylation target MACC1 is druggable by approved MEK1 inhibitors to restrict colorectal cancer metastasis. Oncogene. 2021;40(34):5286-5301doi: 10.1038/s41388-021-01917-z.
Kobelt, D., Perez-Hernandez, D., Fleuter, C., Dahlmann, M., Zincke, F., Smith, J., Migotti, R., Popp, O., Burock, S., Walther, W., Dittmar, G., Mertins, P., & Stein, U. (2021). The newly identified MEK1 tyrosine phosphorylation target MACC1 is druggable by approved MEK1 inhibitors to restrict colorectal cancer metastasis. Oncogene, 40(34), 5286-5301. https://doi.org/10.1038/s41388-021-01917-z
Kobelt, Dennis, et al. "The newly identified MEK1 tyrosine phosphorylation target MACC1 is druggable by approved MEK1 inhibitors to restrict colorectal cancer metastasis." Oncogene vol. 40,34 (2021): 5286-5301. doi: https://doi.org/10.1038/s41388-021-01917-z
Kobelt D, Perez-Hernandez D, Fleuter C, Dahlmann M, Zincke F, Smith J, Migotti R, Popp O, Burock S, Walther W, Dittmar G, Mertins P, Stein U. The newly identified MEK1 tyrosine phosphorylation target MACC1 is druggable by approved MEK1 inhibitors to restrict colorectal cancer metastasis. Oncogene. 2021 Aug;40(34):5286-5301. doi: 10.1038/s41388-021-01917-z. Epub 2021 Jul 10. PMID: 34247190; PMCID: PMC8390371.
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Oncogene. 2021 Aug;40(34):5286-5301. doi: 10.1038/s41388-021-01917-z. Epub 2021 Jul 10.

The newly identified MEK1 tyrosine phosphorylation target MACC1 is druggable by approved MEK1 inhibitors to restrict colorectal cancer metastasis.

Oncogene

Dennis Kobelt, Daniel Perez-Hernandez, Claudia Fleuter, Mathias Dahlmann, Fabian Zincke, Janice Smith, Rebekka Migotti, Oliver Popp, Susen Burock, Wolfgang Walther, Gunnar Dittmar, Philipp Mertins, Ulrike Stein

Affiliations

  1. Translational Oncology of Solid Tumors, Experimental and Clinical Research Center, Charité-Universitätsmedizin Berlin and Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany.
  2. German Cancer Consortium (DKTK), Heidelberg, Germany.
  3. Mass Spectrometry Core Unit, Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany.
  4. Proteome and Genome Research Laboratory, Luxembourg Institute of Health, Strassen, Luxembourg.
  5. Berlin Institute of Health (BIH), Berlin, Germany.
  6. Charité Comprehensive Cancer Center, Charité-Universitätsmedizin Berlin, Berlin, Germany.
  7. Translational Oncology of Solid Tumors, Experimental and Clinical Research Center, Charité-Universitätsmedizin Berlin and Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany. [email protected].
  8. German Cancer Consortium (DKTK), Heidelberg, Germany. [email protected].

PMID: 34247190 PMCID: PMC8390371 DOI: 10.1038/s41388-021-01917-z

Abstract

Cancer metastasis causes >90% of cancer deaths and remains a major treatment challenge. Here we deciphered the impact of tyrosine phosphorylation of MACC1, a causative driver for cancer metastasis, for cancer cell signaling and novel interventions to restrict cancer metastasis. We identified MACC1 as new MEK1 substrate. MEK1 directly phosphorylates MACC1, leading to accelerated and increased ERK1 activation. Mutating in silico predicted hierarchical MACC1 tyrosine phosphorylation sites abrogates MACC1-induced migration, invasion, and MET expression, a transcriptional MACC1 target. Targeting MEK1 by RNAi or clinically applicable MEK1 inhibitors AZD6244 and GSK1120212 reduces MACC1 tyrosine phosphorylation and restricts MACC1-induced metastasis formation in mice. Although MEK1 levels, contrary to MACC1, are not of prognostic relevance for CRC patients, MEK1 expression was found indispensable for MACC1-induced metastasis. This study identifies MACC1 as new MEK1 substrate for tyrosine phosphorylation decisively impacting cell motility, tumor growth, and metastasis. Thus, MAP kinase signaling is not linear leading to ERK activation, but branches at the level of MEK1. This fundamental finding opens new therapeutic options for targeting the MEK1/MACC1 axis as novel vulnerability in patients at high risk for metastasis. This might be extended from CRC to further solid tumor entities.

© 2021. The Author(s).

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