Efficacy of MS-275, a selective inhibitor of class I histone deacetylases, in human colon cancer models.
N-(2-aminophenyl)-4-[N-(pyridine-3yl-methoxy-carbonyl) aminomethyl] benzamide (MS-275) is a second generation histone deacetylase (HDAC) inhibitor with significant anti-tumor efficacy currently in clinical development. We investigated the effect of MS-275 treatment on various colon cancer cell lines, as well as on mouse xenograft models derived from human colorectal cancer. MS-275 exerted strong anti-proliferative effects in five cell lines and increased the acetylation of histones 3 and 4. In vivo testing of the compound in eight different models of human colon cancer derived from primary colorectal cancers or from established cell lines revealed that five models were responders, two non-responders and one an anti-responder. Gene expression profiles were determined in order to identify genes and pathways differentially regulated upon MS-275 treatment in responder versus non-responder models. Principle component analysis revealed a correlation of the anti-tumor efficacy with the sub-clustering of the MS-275 treatment groups in 7 out of 8 models. Although the overall gene expression pattern was rather unique for each individual model, 129 genes were significantly up- and 58 genes significantly down-regulated in at least 2 out of 5 responder models in response to MS-275 treatment. We identified potential biomarkers for response to MS-275, such as PRA1, MYADM and PALM2-AKAP2 which were up-regulated in all responder models and down-regulated or unchanged in all non-responder models. Our results provide a starting point for the development of clinically relevant biomarkers for predicting a response to MS-275 and the understanding of the mode of action of this HDAC inhibitor.
Bracker
Tomke Ute
TU
Global Drug Discovery, Therapeutic Research Group Oncology, Bayer Schering Pharma AG, 13353 Berlin, Germany.
Sommer
Anette
A
Fichtner
Iduna
I
Faus
Hortensia
H
Haendler
Bernard
B
Hess-Stumpp
Holger
H
D000107:Acetylation; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001549:Benzamides / Q000494:pharmacology*; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D016000:Cluster Analysis; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D053263:Gene Regulatory Networks / Q000187:drug effects; D045325:HCT116 Cells; D019073:HT29 Cells; D056464:Histone Deacetylase 2 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006657:Histones / Q000378:metabolism*; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D008819:Mice, Nude; D020411:Oligonucleotide Array Sequence Analysis; D025341:Principal Component Analysis; D011725:Pyridines / Q000494:pharmacology*; D013997:Time Factors; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D001549:Benzamides; D014408:Biomarkers, Tumor; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D011725:Pyridines; C118739:entinostat; C533423:HDAC2 protein, human; D056464:Histone Deacetylase 2