Synergistic antileukemic therapies in NOTCH1-induced T-ALL.
Proc Natl Acad Sci U S A
; 114(8): 2006-2011, 2017 02 21.
Article
in En
| MEDLINE
| ID: mdl-28174276
ABSTRACT
The Notch1 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.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Protein Biosynthesis
/
Antineoplastic Combined Chemotherapy Protocols
/
Drug Resistance, Neoplasm
/
Enzyme Inhibitors
/
Receptor, Notch1
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Amyloid Precursor Protein Secretases
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Precursor T-Cell Lymphoblastic Leukemia-Lymphoma
Type of study:
Prognostic_studies
Limits:
Animals
/
Humans
Language:
En
Journal:
Proc Natl Acad Sci U S A
Year:
2017
Document type:
Article