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Network and Computational Drug Repurposing Analysis for c-Myc Inhibition in Burkitt Lymphoma
Yongmin Lee1, Seungyoon Nam2,3
1Department of Health Sciences and Technology, Gachon Advanced Institute for Health Sciences and Technology (GAIHST), Gachon University, Incheon, Republic of Korea.
Background/Aim:
The treatment rate of Burkitt lymphoma (BL) is still low in low-income countries and among elderly patients. The c-Myc dysregulation induced by mutations is one of the characteristics of BL. However, studies on the downstream signaling pathways of c-Myc are still lacking. This study aimed to identify the signaling pathways regulated by c-Myc.
Materials And Methods:
Network and gene set analyses using c-Myc inhibition (i.e., c-Myc knock-down and c-Myc inhibitor treatment) transcriptome datasets for BL cell lines were performed to determine the pathways regulated by c-Myc. In addition, computational drug repurposing was used to identify drugs that can regulate c-Myc downstream signaling pathway.
Results:
Computational drug repurposing revealed that the ERK/MAPK signaling pathway is regulated by c-Myc in BL and that this pathway can be modulated by vorinostat. Furthermore, in the pharmacogenomics database, vorinostat showed a cell viability half-maximal inhibitory concentration of less than 2 μM in the BL cell lines.
Conclusion:
The downstream signaling pathway regulated by c-Myc and the drug that can modulate this pathway is presented for the first time.
Insights
This study identifies the ERK/MAPK pathway as a key target regulated by c-Myc in Burkitt lymphoma (BL). Vorinostat effectively modulates this pathway, offering a potential new therapeutic strategy for BL.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacogenomics
Background:
- Burkitt lymphoma (BL) has low treatment rates, particularly in low-income countries and among the elderly.
- c-Myc dysregulation is a hallmark of BL, but its downstream pathways remain understudied.
- Identifying c-Myc-regulated pathways is crucial for developing novel BL therapies.
Purpose of the Study:
- To identify signaling pathways regulated by c-Myc in Burkitt lymphoma.
- To discover potential therapeutic agents targeting c-Myc downstream signaling.
Main Methods:
- Network and gene set analyses of transcriptome data from BL cell lines with c-Myc inhibition.
- Computational drug repurposing to identify modulators of c-Myc downstream pathways.
Main Results:
- The ERK/MAPK signaling pathway was identified as being regulated by c-Myc in BL.
- Vorinostat was computationally repurposed and shown to modulate the ERK/MAPK pathway.
- Vorinostat demonstrated potent efficacy with a half-maximal inhibitory concentration (IC50) < 2 μM in BL cell lines.
Conclusions:
- This study presents the first identification of a c-Myc-regulated downstream signaling pathway in BL.
- Vorinostat emerges as a promising drug candidate for modulating this pathway in BL treatment.
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