Genome-scale integration of transcriptome and metabolome unveils squalene synthase and dihydrofolate reductase as targets against AML cells resistant to chemotherapy

  • The development of resistance to chemotherapeutic agents, such as Doxorubicin (DOX) and cytarabine (AraC), is one of the greatest challenges to the successful treatment of Acute Myeloid Leukemia (AML). Such acquisition is often underlined by a metabolic reprogramming that can provide a therapeutic opportunity, as it can lead to the emergence of vulnerabilities and dependencies to be exploited as targets against the resistant cells. In this regard, genome-scale metabolic models (GSMMs) have emerged as powerful tools to integrate multiple layers of data to build cancer-specific models and identify putative metabolic vulnerabilities. Here, we use genome-scale metabolic modelling to reconstruct a GSMM of the THP1 AML cell line and two derivative cell lines, one with acquired resistance to AraC and the second with acquired resistance to DOX. We also explore how, adding to the transcriptomic layer, the metabolomic layer enhances the selectivity of the resulting condition specific reconstructions. The resulting models enabled us to identify and experimentally validate that drug-resistant THP1 cells are sensitive to the FDA-approved antifolate methotrexate. Moreover, we discovered and validated that the resistant cell lines could be selectively targeted by inhibiting squalene synthase, providing a new and promising strategy to directly inhibit cholesterol synthesis in AML drug resistant cells.
Metadaten
Author:Effrosyni KarakitsouORCiD, Carles FoguetORCiD, Miriam Guadalupe Contreras MostazoORCiDGND, Nina Susanne KurrleORCiDGND, Frank SchnütgenORCiDGND, Martin MichaelisORCiDGND, Jindrich CinatlORCiDGND, Silvia MarinORCiD, Marta CascanteORCiD
URN:urn:nbn:de:hebis:30:3-779883
DOI:https://doi.org/10.1016/j.csbj.2021.06.049
ISSN:2001-0370
Parent Title (English):Computational and structural biotechnology journal
Publisher:Elsevier
Place of publication:Amsterdam
Document Type:Article
Language:English
Date of Publication (online):2021/07/23
Date of first Publication:2021/07/08
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2024/04/10
Tag:Acute Myeloid Leukemia (AML); Drug resistance; Drug targets; Metabolic models; Metabolic vulnerabilities
Volume:19
Page Number:8
First Page:4059
Last Page:4066
HeBIS-PPN:520909127
Institutes:Medizin
Dewey Decimal Classification:5 Naturwissenschaften und Mathematik / 57 Biowissenschaften; Biologie / 570 Biowissenschaften; Biologie
6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Sammlungen:Universitätspublikationen
Licence (German):License LogoCreative Commons - CC BY-NC-ND - Namensnennung - Nicht kommerziell - Keine Bearbeitungen 4.0 International