Department of Hematology, Zhongnan Hospital of Wuhan University, Wuhan, P. R. China.
Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Wuhan University, Wuhan, P. R. China.
Carcinogenesis. 2021 Apr 17;42(3):448-460. doi: 10.1093/carcin/bgaa119.
Deregulation of v-myc avian myelocytomatosis viral oncogene homolog (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-acute lymphoblastic leukemia) 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-acute lymphoblastic leukemia 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.
v-myc 禽成髓细胞瘤病毒致癌基因同源物（MYC）的失调发生在广泛的人类癌症中，通常预示着预后不良和对治疗的耐药性。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。细胞周期检查点激酶 1（CHK1）是一种蛋白激酶，可协调 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-急性淋巴细胞白血病）和 N-MYC 驱动的神经母细胞瘤作为模型系统，我们揭示 c-MYC 和 N-MYC 均可直接与 CHK1 基因座结合并激活其转录。CHIR-124 是一种选择性 CHK1 抑制剂，可损害细胞活力，并在 MYC 过表达细胞中与 mTOR 抑制剂 rapamycin 产生显著协同致死作用。在机制上，rapamycin 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）失活，CAD 是从头嘧啶合成的前三个步骤中的必需酶，并恶化了 CHIR-124 诱导的复制应激。我们进一步证明，双重治疗可抑制体内 T-急性淋巴细胞白血病和神经母细胞瘤的进展。这些结果表明，同时靶向 CHK1 和 mTOR 作为一种新的、强大的 MYC 介导的肿瘤联合治疗模式。
