Elevated activity of mTOR is associated with poor prognosis and higher incidence of relapse in B-cell acute lymphoblastic leukemia (B-ALL). Thus, ongoing clinical trials are testing mTOR inhibitors in combination with chemotherapy in B-ALL. However, the combination of mTOR inhibitors with standard of care chemotherapy drugs has not been studied extensively in high-risk B-ALL subtypes. Therefore, we tested whether mTOR inhibition can augment the efficacy of current chemotherapy agents in Ph+ and Ph-like B-ALL models. Surprisingly, inhibiting mTOR complex 1 (mTORC1) protected B-ALL cells from killing by methotrexate and 6-mercaptopurine, two antimetabolite drugs used in maintenance chemotherapy. The cytoprotective effects correlated with decreased cell-cycle progression and were recapitulated using cell-cycle inhibitors, palbociclib or aphidicolin. Dasatinib, a tyrosine kinase inhibitor currently used in Ph+ patients, inhibits ABL kinase upstream of mTOR. Dasatinib resistance is mainly caused by ABL kinase mutations, but is also observed in a subset of ABL unmutated cases. We identified dasatinib-resistant Ph+ cell lines and patient samples in which dasatinib can effectively reduce ABL kinase activity and mTORC1 signaling without causing cell death. In these cases, dasatinib protected leukemia cells from killing by 6-mercaptopurine. Using xenograft models, we observed that mTOR inhibition or dasatinib increased the numbers of leukemia cells that emerge after cessation of chemotherapy treatment. These results demonstrate that inhibitors targeting mTOR or upstream signaling nodes should be used with caution when combined with chemotherapeutic agents that rely on cell-cycle progression to kill B-ALL cells. Mol Cancer Ther; 16(9); 1942–53. ©2017 AACR .

中文翻译：

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mTORC1抑制诱导对Ph +和Ph样B-ALL的甲氨蝶呤和6-巯基嘌呤的抗性

mTOR活性升高与B细胞急性淋巴细胞白血病（B-ALL）的不良预后和较高的复发率相关。因此，正在进行的临床试验正在结合B-ALL对mTOR抑制剂和化学疗法进行测试。然而，尚未在高风险B-ALL亚型中广泛研究mTOR抑制剂与标准护理化疗药物的组合。因此，我们测试了mTOR抑制是否可以增强Ph +和Ph样B-ALL模型中当前化疗药物的疗效。出人意料的是，抑制mTOR复合物1（mTORC1）保护B-ALL细胞免受甲氨蝶呤和6-巯基嘌呤的杀伤，这是两种用于维持化疗的抗代谢药物。细胞保护作用与细胞周期进程减少有关，并使用细胞周期抑制剂palbociclib或蚜虫碱重新概括。Dasatinib是目前在Ph +患者中使用的一种酪氨酸激酶抑制剂，可抑制mTOR上游的ABL激酶。达沙替尼耐药主要是由ABL激酶突变引起的，但在ABL未突变的病例中也观察到了耐药性。我们确定了达沙替尼耐药的Ph +细胞系和患者样品，其中达沙替尼可以有效降低ABL激酶活性和mTORC1信号转导而不会引起细胞死亡。在这些情况下，达沙替尼可保护白血病细胞免受6-巯基嘌呤的杀伤。使用异种移植模型，我们观察到mTOR抑制或dasatinib增加了停止化疗后出现的白血病细胞的数量。这些结果表明，与依赖细胞周期进程杀死B-ALL细胞的化学治疗剂联合使用时，应谨慎使用靶向mTOR或上游信号转导点的抑制剂。分子癌疗法；16（9）; 1942–53。©2017 AACR。