Autoren:	More, Piyush Mekontso Ngaffo, Joëlle Aurelie Goedtel-Armbrust, Ute Hähnel, Patricia S. Hartwig, Udo F. Kindler, Thomas Wojnowski, Leszek
Titel:	Transcriptional response to standard AML drugs identifies synergistic combinations
Online-Publikationsdatum:	19-Feb-2024
Erscheinungsdatum:	2023
Sprache des Dokuments:	Englisch
Zusammenfassung/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-Sachgruppe:	610 Medizin 610 Medical sciences
Veröffentlichende Institution:	Johannes Gutenberg-Universität Mainz
Organisationseinheit:	FB 04 Medizin
Veröffentlichungsort:	Mainz
ROR:	https://ror.org/023b0x485
DOI:	http://doi.org/10.25358/openscience-10038
Version:	Published version
Publikationstyp:	Zeitschriftenaufsatz
Weitere Angaben zur Dokumentart:	Scientific article
Nutzungsrechte:	CC BY
Informationen zu den Nutzungsrechten:	https://creativecommons.org/licenses/by/4.0/
Zeitschrift:	International journal of molecular sciences 24 16
Seitenzahl oder Artikelnummer:	12926
Verlag:	MDPI
Verlagsort:	Basel
Erscheinungsdatum:	2023
ISSN:	1422-0067
DOI der Originalveröffentlichung:	10.3390/ijms241612926
Enthalten in den Sammlungen:	DFG-491381577-G