TY  - JOUR
A1  - Karakitsou, Effrosyni
A1  - Foguet, Carles
A1  - Contreras Mostazo, Miriam Guadalupe
A1  - Kurrle, Nina Susanne
A1  - Schnütgen, Frank
A1  - Michaelis, Martin
A1  - Cinatl, Jindrich
A1  - Marin, Silvia
A1  - Cascante, Marta
T1  - Genome-scale integration of transcriptome and metabolome unveils squalene synthase and dihydrofolate reductase as targets against AML cells resistant to chemotherapy
T2  - Computational and structural biotechnology journal
N2  - 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.
KW  - Metabolic models
KW  - Drug resistance
KW  - Acute Myeloid Leukemia (AML)
KW  - Metabolic vulnerabilities
KW  - Drug targets
Y1  - 2021
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/77988
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-779883
SN  - 2001-0370
VL  - 19
SP  - 4059
EP  - 4066
PB  - Elsevier
CY  - Amsterdam
ER  -