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 the greatest challenges successful treatment Acute Myeloid Leukemia (AML). Such acquisition often underlined by a metabolic reprogramming that can provide therapeutic opportunity, it lead emergence vulnerabilities dependencies be exploited targets against resistant cells. In this regard, genome-scale models (GSMMs) have emerged powerful tools integrate multiple layers data build cancer-specific identify putative vulnerabilities. Here, we use modelling reconstruct GSMM THP1 AML cell line two derivative lines, with acquired AraC second DOX. We also explore how, adding transcriptomic layer, metabolomic layer enhances selectivity resulting condition specific reconstructions. enabled us experimentally validate drug-resistant cells are sensitive FDA-approved antifolate methotrexate. Moreover, discovered validated lines could selectively targeted inhibiting squalene synthase, providing new promising strategy directly inhibit cholesterol synthesis in drug