Synergistic antileukemic therapies in NOTCH1-induced T-ALL.
Marta Sanchez-MartinAlberto Ambesi-ImpiombatoYue QinDaniel HerranzMukesh BansalTiziana GirardiElisabeth PaiettaMartin S TallmanJacob M RoweKim De KeersmaeckerAndrea CalifanoAdolfo A FerrandoPublished in: Proceedings of the National Academy of Sciences of the United States of America (2017)
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.
Keyphrases
- cell proliferation
- acute lymphoblastic leukemia
- clinical trial
- binding protein
- poor prognosis
- cancer therapy
- transcription factor
- protein protein
- dna methylation
- gene expression
- drug delivery
- small molecule
- acute myeloid leukemia
- diabetic rats
- long non coding rna
- endothelial cells
- replacement therapy
- combination therapy