Synergistic Targeting of CHK1 and mTOR in MYC-driven tumors.
Synergistic Targeting of CHK1 and mTOR in MYC-driven tumors.
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DOI：
10.1093/carcin/bgaa119
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发表时间：
2020-11
期刊：
影响因子：
4.7
通讯作者：
Xiaoxue Song;Liyuan Wang;Tianci Wang;Juncheng Hu;Jingchao Wang;Rongfu Tu;H. Su;Jue Jiang;Guoliang Qing;Hudan Liu
中科院分区：
文献类型：
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作者：
Xiaoxue Song;Liyuan Wang;Tianci Wang;Juncheng Hu;Jingchao Wang;Rongfu Tu;H. Su;Jue Jiang;Guoliang Qing;Hudan Liu
MYC的失调发生在广泛的人类癌症中，并且通常预测不良预后和对治疗的抗性。然而，直接靶向致癌MYC仍然不成功，间接抑制MYC成为一种有前途的方法。检查点激酶1（Checkpoint kinase 1，CHK 1）是一种蛋白激酶，其协调G2/M细胞周期检查点并保护癌细胞免受过度复制应激。使用c-MYC介导的T细胞急性淋巴细胞白血病（T-ALL）和N-MYC驱动的神经母细胞瘤作为模型系统，我们揭示了c-MYC和N-MYC直接结合CHK 1位点并激活其转录。CHIR-124，一种选择性CHK 1抑制剂，损害细胞活力，并与mTOR抑制剂雷帕霉素在MYC过表达细胞中诱导显著的协同致死性。从机制上讲，雷帕霉素使氨甲酰磷酸合成酶2、天冬氨酸转氨甲酰酶和二氢乳清酸酶（CAD）（从头嘧啶合成的前三个步骤的必需酶）失活，并使CHIR-124诱导的复制应激恶化。我们进一步证明，双重治疗阻止T-ALL和神经母细胞瘤的进展在体内。这些结果表明，同时靶向CHK 1和mTOR是MYC介导的肿瘤的一种新的强大的联合治疗方式。
Deregulation of MYC occurs in a broad range of human cancers and often predicts poor prognosis and resistance to therapy. However, directly targeting oncogenic MYC remains unsuccessful, and indirectly inhibiting MYC emerges as a promising approach. Checkpoint kinase 1 (CHK1) is a protein kinase that coordinates the G2/M cell cycle checkpoint and protects cancer cells from excessive replicative stress. Using c-MYC-mediated T-cell acute lymphoblastic leukemia (T-ALL) and N-MYC-driven neuroblastoma as model systems, we reveal that both c-MYC and N-MYC directly bind to the CHK1 locus and activate its transcription. CHIR-124, a selective CHK1 inhibitor, impairs cell viability and induces remarkable synergistic lethality with mTOR inhibitor rapamycin in MYC-overexpressing cells. Mechanistically, rapamycin inactivates carbamoyl-phosphate synthetase 2, aspartate transcarbamoylase, and dihydroorotase (CAD), the essential enzyme for the first three steps of de novo pyrimidine synthesis, and deteriorates CHIR-124-induced replicative stress. We further demonstrate that dual treatments impede T-ALL and neuroblastoma progression in vivo. These results suggest simultaneous targeting of CHK1 and mTOR as a novel and powerful co-treatment modality for MYC-mediated tumors.