Authors:	More, Piyush Mekontso Ngaffo, Joëlle Aurelie Goedtel-Armbrust, Ute Hähnel, Patricia S. Hartwig, Udo F. Kindler, Thomas Wojnowski, Leszek
Title:	Transcriptional response to standard AML drugs identifies synergistic combinations
Online publication date:	19-Feb-2024
Year of first publication:	2023
Language:	english
Abstract:	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.
DDC:	610 Medizin 610 Medical sciences
Institution:	Johannes Gutenberg-Universität Mainz
Department:	FB 04 Medizin
Place:	Mainz
ROR:	https://ror.org/023b0x485
DOI:	http://doi.org/10.25358/openscience-10038
Version:	Published version
Publication type:	Zeitschriftenaufsatz
Document type specification:	Scientific article
License:	CC BY
Information on rights of use:	https://creativecommons.org/licenses/by/4.0/
Journal:	International journal of molecular sciences 24 16
Pages or article number:	12926
Publisher:	MDPI
Publisher place:	Basel
Issue date:	2023
ISSN:	1422-0067
Publisher DOI:	10.3390/ijms241612926
Appears in collections:	DFG-491381577-G