Please use this identifier to cite or link to this item:
http://doi.org/10.25358/openscience-10038
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 |
Files in This Item:
File | Description | Size | Format | ||
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transcriptional_response_to_s-20240205160101720.pdf | 4.81 MB | Adobe PDF | View/Open |