Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts.
Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, Massachusetts.
Clin Cancer Res. 2019 Jan 1;25(1):312-324. doi: 10.1158/1078-0432.CCR-18-0867. Epub 2018 Sep 17.
Effective targeted therapies are lacking for refractory and relapsed T-cell acute lymphoblastic leukemia (T-ALL). Suppression of the NOTCH pathway using gamma-secretase inhibitors (GSI) is toxic and clinically not effective. The goal of this study was to identify alternative therapeutic strategies for T-ALL.
We performed a comprehensive analysis of our high-throughput drug screen across hundreds of human cell lines including 15 T-ALL models. We validated and further studied the top hit, navitoclax (ABT-263). We used multiple human T-ALL cell lines as well as primary patient samples, and performed both experiments and studies on patient-derived xenograft models.
We found that T-ALL are hypersensitive to navitoclax, an inhibitor of BCL2 family of antiapoptotic proteins. Importantly, GSI-resistant T-ALL are also susceptible to navitoclax. Sensitivity to navitoclax is due to low levels of MCL-1 in T-ALL. We identify an unsuspected regulation of mTORC1 by the NOTCH pathway, resulting in increased MCL-1 upon GSI treatment. Finally, we show that pharmacologic inhibition of mTORC1 lowers MCL-1 levels and further sensitizes cells to navitoclax and leads to tumor regressions .
Our results support the development of navitoclax, as single agent and in combination with mTOR inhibitors, as a new therapeutic strategy for T-ALL, including in the setting of GSI resistance.
对于难治性和复发性 T 细胞急性淋巴细胞白血病（T-ALL），缺乏有效的靶向治疗方法。使用 γ-分泌酶抑制剂（GSI）抑制 NOTCH 通路具有毒性，且在临床上无效。本研究的目的是确定治疗 T-ALL 的替代治疗策略。
我们对包括 15 个 T-ALL 模型在内的数百个人类细胞系进行了高通量药物筛选的全面分析。我们验证并进一步研究了排名最高的药物 navitoclax（ABT-263）。我们使用多种人 T-ALL 细胞系和原发性患者样本，并在患者来源的异种移植模型上进行了实验和研究。
我们发现 T-ALL 对 navitoclax（一种 BCL2 家族抗凋亡蛋白抑制剂）高度敏感。重要的是，GSI 耐药的 T-ALL 也易受 navitoclax 影响。对 navitoclax 的敏感性是由于 T-ALL 中 MCL-1 水平较低所致。我们发现 NOTCH 通路对 mTORC1 的调控存在未知机制，导致 GSI 处理后 MCL-1 增加。最后，我们表明，mTORC1 的药理学抑制降低了 MCL-1 水平，进一步增强了细胞对 navitoclax 的敏感性，并导致肿瘤消退。
我们的结果支持将 navitoclax 作为单一药物和与 mTOR 抑制剂联合使用，作为治疗 T-ALL 的新治疗策略，包括在 GSI 耐药的情况下。
