@article{f6f54216842b46dc8f54da553ddebe5f,
title = "Synergistic antileukemic therapies in NOTCH1-induced T-ALL",
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.",
keywords = "Leukemia, NOTCH1, Protein translation, Synergy, T-ALL",
author = "Marta Sanchez-Martin and Alberto Ambesi-Impiombato and Yue Qin and Daniel Herranz and Mukesh Bansal and Tiziana Girardi and Elisabeth Paietta and Tallman, {Martin S.} and Rowe, {Jacob M.} and {De Keersmaecker}, Kim and Andrea Califano and Ferrando, {Adolfo A.}",
note = "Funding Information: We thank the ECOG-ACRIN Cancer Research Group for clinical specimens; J. Aster for the MigR1-NOTCH1 L1601P ΔPEST vector; D. Ron for the pCDNA3 eIF2S1, pCDNA3 eIF2S1-S51A and pCDNA3 eIF2S1-S51D plasmids; P. P. Pandolfi for the Ptenfl conditional knockout mouse; T. Ludwig for the ROSA26Cre-ERT2/+ mouse; S. Indraccolo for xenograft T-ALL cells, R. Baer for helpful discussions and revision of the manuscript; and L. Xu for technical assistance in mouse experiments. This work was supported by the National Institute of Health (Grants R01CA129382 and CA120196 to A.A.F.; Grants CA180827 and CA196172 to E.P.; and CA180820, CA189859, CA14958, CA180791, and CA17145 to ECOG-ACRIN), the Stand Up to Cancer Innovative Research Award (to A.A.F.), the Swim Across America Foundation (to A.A.F.), the William Lawrence and Blanche Hughes Foundation (to A.A.F.), Fonds Wetenschappelijk Onderzoek Vlandereen (G084013) and European Research Council Starting Grant 334946 (to K.D.K.). D.H. is supported by the US National Institutes of Health Grant K99/R00 CA197869 and an Alex Lemonade Stand Foundation Young Investigator grant. M.S.-M. is a postdoctoral fellow funded by the Rally Foundation. Publisher Copyright: {\textcopyright} 2017, National Academy of Sciences. All rights reserved.",
year = "2017",
month = feb,
day = "21",
doi = "10.1073/pnas.1611831114",
language = "English (US)",
volume = "114",
pages = "2006--2011",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
publisher = "National Academy of Sciences",
number = "8",
}