Synergistic antileukemic therapies in NOTCH1 -induced T-ALL
Year: 2017
Type: article
Abstract: gene is a major oncogenic driver and therapeutic target in T-cell acute lymphoblastic leukemia (T-ALL). However, inhibition of NOTCH signaling with γ-secretase inhibitors (GSIs) has shown limited antileukemic activity in clinical trials. Here we performed an expression-based virtual screening to identify highly active antileukemic drugs that synergize with NOTCH1 inhibition in T-ALL. Among these, withaferin A demonstrated the strongest cytotoxic and GSI-synergistic antileukemic effects in vitro and in vivo. Mechanistically, network perturbation analyses showed eIF2A-phosphorylation-mediated inhibition of protein translation as a critical mediator of the antileukemic effects of withaferin A and its interaction with NOTCH1 inhibition. Overall, these results support a role for anti-NOTCH1 therapies and protein translation inhibitor combinations in the treatment of T-ALL.
Language: English
Field: Medicine
Domain: Health Sciences
Open Access status: green
Awards: G1320119874, G1544246282, ECOG-ACRIN Network Group Operations Center, Network Lead Academic Participating Site: Memorial Sloan-Kettering Cancer Center, MINORITY-BASED COMMUNITY ONCOLOGY PROGRAM, G223568039, G2574010377, Storage System for High Performance Computing, Functional dissection of oncogenic enhancers, Centers for Cancer Systems Therapeutics (CaST), ECOG Clinical Trials, G4457201800, High-performance compute cluster for biomedical computing, G5412686921, G5417201949, G608154585, G615183142, G744782498, ECOG-ACRIN INTEGRATED LEUKEMIA TRANSLATIONAL RESEARCH CENTER, G8165423003
OpenAlex ID: W2586523784