Transcriptional Response to Standard AML Drugs Identifies Synergistic Combinations

Unlike genomic alterations, gene expression profiles have not been widely used to refine cancer therapies. We analyzed transcriptional changes in acute myeloid leukemia (AML) cell lines in response to standard first-line AML drugs cytarabine and daunorubicin by means of RNA sequencing. Those changes were highly cell- and treatment-specific. By comparing the changes unique to treatment-sensitive and treatment-resistant AML cells, we enriched for treatment-relevant genes. Those genes were associated with drug response-specific pathways, including calcium ion-dependent exocytosis and chromatin remodeling. Pharmacological mimicking of those changes using EGFR and MEK inhibitors enhanced the response to daunorubicin with minimum standalone cytotoxicity. The synergistic response was observed even in the cell lines beyond those used for the discovery, including a primary AML sample. Additionally, publicly available cytotoxicity data confirmed the synergistic effect of EGFR inhibitors in combination with daunorubicin in all 60 investigated cancer cell lines. In conclusion, we demonstrate the utility of treatment-evoked gene expression changes to formulate rational drug combinations. This approach could improve the standard AML therapy, especially in older patients

Intellectuels et polémiques

Cet ouvrage analyse les différents aspects du phénomène des polémiques - protagonistes, public, thèmes, déroulement, moyens, médias, motifs et enjeux - et dégage, ce faisant, des régularités à travers les époques pour chercher à établir un inventaire de traits récurrents, de rituels propres aux polémiques entre intellectuels.This volume analyzes the different aspects of the controversies’ phenomenon: protagonists, audience, theme, unfolding, means, medias, motifs and stakes. It exposes the presence of regularities through the ages, searching to establish an inventory of recurring traits, rituals specific to controversies between intellectuals