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. 2023 Aug 18;24(16):12926.
doi: 10.3390/ijms241612926.

Transcriptional Response to Standard AML Drugs Identifies Synergistic Combinations

Piyush More  1 , Joëlle Aurelie Mekontso Ngaffo  1   2 , Ute Goedtel-Armbrust  1 , Patricia S Hähnel  3   4 , Udo F Hartwig  4   5 , Thomas Kindler  3   4 , Leszek Wojnowski  1
Affiliations

Transcriptional Response to Standard AML Drugs Identifies Synergistic Combinations

Piyush More et al. Int J Mol Sci. .

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.

Keywords: AML; combination therapy; cytarabine; daunorubicin; gene expression changes; transcription.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Response of AML cell lines to standard drugs. (A) Percentage cell death and (B) number of gene expression change in 3 AML cell lines in response to treatments with cytarabine, daunorubicin, and their combination for 24 h compared to DMSO. Percentage cell death was measured using CellTiter-Glo assay, and gene expression changes were identified from RNA-Seq.
Figure 2
Figure 2
Cell-wise overlapping gene expression changes. The Venn diagrams (unscaled) represent the overlaps among gene expression changes after treatment with cytarabine, daunorubicin, and the combination for 24 h in each AML cell line. In each panel, gene expression changes from all 3 treatments account for 100%.
Figure 3
Figure 3
Pathway enrichment analysis. (A) Biological processes are commonly affected by all three treatments. The bars represent the number of genes associated with a particular pathway averaged across all three treatments. (B) Biological processes related to down-regulated and (C) up-regulated genes after daunorubicin treatment for 24 h.
Figure 4
Figure 4
Gene network enrichment map. A network organizing enriched biological processes into a network with edges connecting overlapping gene sets. The network clustered mutually overlapping gene sets together. The clusters represent enriched biological processes after daunorubicin treatment in 3 AML cell lines. The highlighted cluster (dashed red ellipse) indicates the activation of PI3K pathway-related processes in only HL60 cells.
Figure 5
Figure 5
Predicted daunorubicin combinations and their validation. (A) Top 5 drug classes predicted to exhibit either synergistic or antagonist response in combination with daunorubicin. Predicted combinations showed a similar transcriptional response to the DNRResponse profile and an opposite transcriptional response to the DNRResist profile. (B) Contour plots with the demonstrated effect of combining daunorubicin with MEK inhibitor PD98059 in HL60 and primary AML cells, respectively. (C) Pie charts represent either synergistic or antagonist response of 60 cancer cell lines to combining daunorubicin with either EGFR or HDAC inhibitors. Data was obtained from the NCI ALMANAC drug combination screen.
Figure 5
Figure 5
Predicted daunorubicin combinations and their validation. (A) Top 5 drug classes predicted to exhibit either synergistic or antagonist response in combination with daunorubicin. Predicted combinations showed a similar transcriptional response to the DNRResponse profile and an opposite transcriptional response to the DNRResist profile. (B) Contour plots with the demonstrated effect of combining daunorubicin with MEK inhibitor PD98059 in HL60 and primary AML cells, respectively. (C) Pie charts represent either synergistic or antagonist response of 60 cancer cell lines to combining daunorubicin with either EGFR or HDAC inhibitors. Data was obtained from the NCI ALMANAC drug combination screen.
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