Drug Mechanism Of Action Probed By Pathway Gene Expressions And Growth Inhibition Response

One general approach to identify target-specific agents as a basis for understanding a drug's mechanism of action (MOA) is to relate gene expression patterns measured across a diverse set of tumor cell models to drug-induced chemosensitivity of these same cells (17,40,41,42,43,44,45,46, 47,48,49,50,51,52,53). Previous efforts using this strategy have focused mainly on finding causes of drug resistance (40, 41, 42, 49,54,55). Gene expression signatures have also been used as surrogate markers of cellular states, for example, to identify agents that induce the differentiation of acute myeloid leukemia cells (56). However, nearly all of these investigations have been based on single gene expression-drug response relationships, whereas complex interactions between a drug and highly interconnected biological networks may not be reflected solely by the state of any one gene. Moreover, quantitative assessments that associate significant correlations between gene expression levels and drug sensitivity as a basis for validating a biologically significant connection are not yet a standard practice.

Gene expression patterns across the NCI60 can be organized in terms of predefined pathways or functional categories annotated by KEGG, BioCarta, and Gene Ontology. These gene annotations are used to link pathways to drug responses through correlations between pathway gene expression patterns and drug GI50 response profiles clustered in SOM clades. Implicit in this design is the assumption that cytotoxicity profiles most strongly associated with gene expression profiles for genes within a defined pathway are valid indications of a test compound perturbing the pathway; conversely, the genes in the pathway would play major roles in dictating the cytotoxic activity of the compound. Our approach associates drug responses in each clade with subsets of pathways. Assignment of putative MOAs for agents clustered in each SOM response region are then postulated to involve pathways that can be significantly correlated with these agents.

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