Synergistic antileukemic therapies inNOTCH1-induced T-ALL.
TheNotch1gene 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.
Institute for Cancer Genetics, Columbia University, New York, NY 10032.
Marta
M
Sanchez-Martin
Institute for Cancer Genetics, Columbia University, New York, NY 10032.
Alberto
A
Ambesi-Impiombato
Institute for Cancer Genetics, Columbia University, New York, NY 10032.
Yue
Y
Qin
Institute for Cancer Genetics, Columbia University, New York, NY 10032.
Daniel
D
Herranz
Department of Systems Biology, Columbia University, New York, NY 10032.
Mukesh
M
Bansal
KU Leuven, University of Leuven, 3000 Leuven, Belgium.|Department of Oncology, Leuven Cancer Institute, 3000 Leuven, Belgium.
Tiziana
T
Girardi
Montefiore Medical Center, New York, NY 10467.
Elisabeth
E
Paietta
Department of Hematologic Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10065.
Martin S
MS
Tallman
Technion, Israel Institute of Technology, Haifa 3200003, Israel.
Jacob M
JM
Rowe
KU Leuven, University of Leuven, 3000 Leuven, Belgium.|Department of Oncology, Leuven Cancer Institute, 3000 Leuven, Belgium.
Kim
0000-0002-7420-9531
K
De Keersmaecker
Department of Systems Biology, Columbia University, New York, NY 10032.
Andrea
A
Califano
Institute for Cancer Genetics, Columbia University, New York, NY 10032; af2196@columbia.edu.|Department of Pediatrics, Columbia University, New York, NY 10032.|Department of Pathology, Columbia University, New York, NY 10032.
Adolfo A
AA
Ferrando
D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D020869:Gene Expression Profiling; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D058990:Molecular Targeted Therapy / Q000379:methods; D010766:Phosphorylation / Q000187:drug effects; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000473:pathology; D014176:Protein Biosynthesis / Q000187:drug effects*; D051881:Receptor, Notch1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D054358:Withanolides / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays; D019892:eIF-2 Kinase / Q000378:metabolism
D004791:Enzyme Inhibitors; C497761:NOTCH1 protein, human; D051881:Receptor, Notch1; D054358:Withanolides; D019892:eIF-2 Kinase; D053829:Amyloid Precursor Protein Secretases; C009684:withaferin A
NOTCH1; T-ALL; leukemia; protein translation; synergy