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Open AccessArticle

Characterization of the Menin-MLL Interaction as Therapeutic Cancer Target

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Bayer AG, Innovation Campus Berlin, Research & Development, Pharmaceuticals, Muellerstrasse 178, D-13353 Berlin, Germany
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Bayer AG, Research & Development, Pharmaceuticals, Muellerstrasse 178, D-13353 Berlin, Germany
*
Author to whom correspondence should be addressed.
Current address: Institut de Recherches Servier, 125 Chemin de Ronde, 78290 Croissy-sur-Seine, France.
Cancers 2020, 12(1), 201; https://doi.org/10.3390/cancers12010201
Received: 12 December 2019 / Revised: 7 January 2020 / Accepted: 9 January 2020 / Published: 14 January 2020
Inhibiting the interaction of menin with the histone methyltransferase MLL1 (KMT2A) has recently emerged as a novel therapeutic strategy. Beneficial therapeutic effects have been postulated in leukemia, prostate, breast, liver and in synovial sarcoma models. In those indications, MLL1 recruitment by menin was described to critically regulate the expression of disease associated genes. However, most findings so far rely on single study reports. Here we independently evaluated the pathogenic functions of the menin-MLL interaction in a large set of different cancer models with a potent and selective probe inhibitor BAY-155. We characterized the inhibition of the menin-MLL interaction for anti-proliferation, gene transcription effects, and for efficacy in several in vivo xenografted tumor models. We found a specific therapeutic activity of BAY-155 primarily in AML/ALL models. In solid tumors, we observed anti-proliferative effects of BAY-155 in a surprisingly limited fraction of cell line models. These findings were further validated in vivo. Overall, our study using a novel, highly selective and potent inhibitor, shows that the menin-MLL interaction is not essential for the survival of most solid cancer models. We can confirm that disrupting the menin-MLL complex has a selective therapeutic benefit in MLL-fused leukemia. In solid cancers, effects are restricted to single models and more limited than previously claimed.
Keywords: chemical probe; menin-MLL; target validation; cancer; solid tumor chemical probe; menin-MLL; target validation; cancer; solid tumor
MDPI and ACS Style

Brzezinka, K.; Nevedomskaya, E.; Lesche, R.; Haegebarth, A.; ter Laak, A.; Fernández-Montalván, A.E.; Eberspaecher, U.; Werbeck, N.D.; Moenning, U.; Siegel, S.; Haendler, B.; Eheim, A.L.; Stresemann, C. Characterization of the Menin-MLL Interaction as Therapeutic Cancer Target. Cancers 2020, 12, 201.

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