A systems biology approach to investigate the mechanism of action of trabectedin in a model of myelomonocytic leukemia

• Published in: The pharmacogenomics journal 2018-01, Vol.18 (1), p.56-63
• Main Authors: Mannarino, L, Paracchini, L, Craparotta, I, Romano, M, Marchini, S, Gatta, R, Erba, E, Clivio, L, Romualdi, C, D’Incalci, M, Beltrame, L, Pattini, L
• Format: Article
• Language: English
• Subjects: 13/31; 38/39; 38/61; 38/77; 631/114/2114; 631/67/69; Antineoplastic Agents, Alkylating - therapeutic use; Biology; Biomedical and Life Sciences; Biomedicine; Cell Line, Tumor; Complications and side effects; DNA topoisomerase; Dopamine; Dopamine receptors; Dosage and administration; Drug therapy; Gene Expression; Gene Expression Profiling - methods; Gene Regulatory Networks - drug effects; Genetic aspects; Health aspects; Human Genetics; Humans; Investigations; Irinotecan; Leukemia; Leukemia, Myeloid - drug therapy; Mode of action; Myelomonocytic leukemia; Oncology; Original; original-article; Pharmacotherapy; Psychopharmacology; Studies; Systems Biology - methods; Thioridazine; Trabectedin; Trabectedin - pharmacology; Transcription factors; Transcription, Genetic - drug effects
• ISSN: 1470-269X; 1473-1150
• DOI: 10.1038/tpj.2016.76

This study was designed to investigate the mode of action of trabectedin in myelomonocytic leukemia cells by applying systems biology approaches to mine gene expression profiling data and pharmacological assessment of the cellular effects. Significant enrichment was found in regulons of target genes inferred for specific transcription factors, among which MAFB was the most upregulated after treatment and was central in the transcriptional network likely to be relevant for the specific therapeutic effects of trabectedin against myelomonocytic cells. Using the Connectivity Map, similarity among transcriptional signatures elicited by treatment with different compounds was investigated, showing a high degree of similarity between transcriptional signatures of trabectedin and those of the topoisomerase I inhibitor, irinotecan, and an anti-dopaminergic antagonist, thioridazine. The study highlights the potential importance of systems biology approaches to generate new hypotheses that are experimentally testable to define the specificity of the mechanism of action of drugs.