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...
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-08-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/16/12926 |
| _version_ | 1797584396040011776 |
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| author | Piyush More Joëlle Aurelie Mekontso Ngaffo Ute Goedtel-Armbrust Patricia S. Hähnel Udo F. Hartwig Thomas Kindler Leszek Wojnowski |
| author_facet | Piyush More Joëlle Aurelie Mekontso Ngaffo Ute Goedtel-Armbrust Patricia S. Hähnel Udo F. Hartwig Thomas Kindler Leszek Wojnowski |
| author_sort | Piyush More |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-10T23:52:19Z |
| format | Article |
| id | doaj.art-57dce19a328f4e988c833c238de93eea |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T23:52:19Z |
| publishDate | 2023-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-57dce19a328f4e988c833c238de93eea2023-11-19T01:32:27ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-08-0124161292610.3390/ijms241612926Transcriptional Response to Standard AML Drugs Identifies Synergistic CombinationsPiyush More0Joëlle Aurelie Mekontso Ngaffo1Ute Goedtel-Armbrust2Patricia S. Hähnel3Udo F. Hartwig4Thomas Kindler5Leszek Wojnowski6Department of Pharmacology, University Medical Center, Johannes Gutenberg-University, 55131 Mainz, GermanyDepartment of Pharmacology, University Medical Center, Johannes Gutenberg-University, 55131 Mainz, GermanyDepartment of Pharmacology, University Medical Center, Johannes Gutenberg-University, 55131 Mainz, GermanyUniversity Cancer Center (UCT) Mainz, Johannes Gutenberg-University, 55131 Mainz, GermanyDepartment of Hematology & Medical Oncology, University Medical Center, Johannes Gutenberg-University, 55131 Mainz, GermanyUniversity Cancer Center (UCT) Mainz, Johannes Gutenberg-University, 55131 Mainz, GermanyDepartment of Pharmacology, University Medical Center, Johannes Gutenberg-University, 55131 Mainz, GermanyUnlike 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.https://www.mdpi.com/1422-0067/24/16/12926AMLtranscriptiongene expression changescytarabinedaunorubicincombination therapy |
| spellingShingle | Piyush More Joëlle Aurelie Mekontso Ngaffo Ute Goedtel-Armbrust Patricia S. Hähnel Udo F. Hartwig Thomas Kindler Leszek Wojnowski Transcriptional Response to Standard AML Drugs Identifies Synergistic Combinations International Journal of Molecular Sciences AML transcription gene expression changes cytarabine daunorubicin combination therapy |
| title | Transcriptional Response to Standard AML Drugs Identifies Synergistic Combinations |
| title_full | Transcriptional Response to Standard AML Drugs Identifies Synergistic Combinations |
| title_fullStr | Transcriptional Response to Standard AML Drugs Identifies Synergistic Combinations |
| title_full_unstemmed | Transcriptional Response to Standard AML Drugs Identifies Synergistic Combinations |
| title_short | Transcriptional Response to Standard AML Drugs Identifies Synergistic Combinations |
| title_sort | transcriptional response to standard aml drugs identifies synergistic combinations |
| topic | AML transcription gene expression changes cytarabine daunorubicin combination therapy |
| url | https://www.mdpi.com/1422-0067/24/16/12926 |
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