Sanchez-Martin Marta, Ambesi-Impiombato Alberto, Qin Yue, Herranz Daniel, Bansal Mukesh, Girardi Tiziana, Paietta Elisabeth, Tallman Martin S, Rowe Jacob M, De Keersmaecker Kim, Califano Andrea, Ferrando Adolfo A
Institute for Cancer Genetics, Columbia University, New York, NY 10032.
Department of Systems Biology, Columbia University, New York, NY 10032.
Proc Natl Acad Sci U S A. 2017 Feb 21;114(8):2006-2011. doi: 10.1073/pnas.1611831114. Epub 2017 Feb 7.
The 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.
该基因是T细胞急性淋巴细胞白血病（T-ALL）的主要致癌驱动因子和治疗靶点。然而，在临床试验中，用γ-分泌酶抑制剂（GSIs）抑制NOTCH信号显示出有限的抗白血病活性。在此，我们进行了基于表达的虚拟筛选，以鉴定在T-ALL中与NOTCH1抑制协同作用的高活性抗白血病药物。其中，睡茄素A在体外和体内均表现出最强的细胞毒性和GSI协同抗白血病作用。从机制上讲，网络扰动分析表明，eIF2A磷酸化介导的蛋白质翻译抑制是睡茄素A抗白血病作用及其与NOTCH1抑制相互作用的关键介质。总体而言，这些结果支持抗NOTCH1疗法和蛋白质翻译抑制剂联合应用在T-ALL治疗中的作用。
