GSE136272
Characterization of the menin-MLL interaction as therapeutic cancer target in solid tumor models
Background: Inhibition of the interaction of the scaffold protein menin with the histone methyltransferase MLL1 (KMT2A) has recently emerged as a novel therapeutic strategy in different cancers. Purpose: Here we validate the proposed pathogenic function of the menin-MLL interaction in cancer with a novel probe inhibitor BAY-155. Methods: RNA-seq was used to investigate transcriptional effects of novel BAY-155 probe in thirteen cell lines from a range of solid tumor types. Results: Menin-MLL inhibition by BAY-155 in colorectal (SW1463, LoVo, DLD-1), prostate (22RV1, LNCaP, VCaP), pancreas (PANC-1, MiaPaCa2), breast (BT-474, ZR-75-1, MCF7), bladder (JMSU-1) and kidney (G401) tissue derived cancer cell lines resulted in moderate gene expression changes. Surprisingly, for the reported role of MLL1 as a co-activator of gene expression, inhibition by BAY-155 led predominantly to up-regulation of genes. We could not observe any evidences of an overarching, menin driven expression program, which is in contrast to previous reports for e.g. the Hox gene cluster. Conclusions: Our study adds important critical validation data to the menin-MLL interaction as therapeutic target in solid cancers. By using a more selective and potent inhibitor we propose that the potential therapeutic benefit of disrupting the menin-MLL interaction may be more restricted to specific cancers than previously predicted. Overall design: RNA-sequencing of solid cancers-derived cell lines treated with BAY-155 inhibitor, combination of steroid hormone (ß-Estradiol or R1881 for breast and prostate cancer cell lines respectively) and BAY-155 or DMSO control.