The combination of CHK1 inhibitor with G-CSF overrides cytarabine resistance in human acute myeloid leukemia.
The combination of CHK1 inhibitor with G-CSF overrides cytarabine resistance in human acute myeloid leukemia.
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DOI：
10.1038/s41467-017-01834-4
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发表时间：
2017-11-22
影响因子：
16.6
通讯作者：
Bonnet D
中科院分区：
文献类型：
--
作者：
Di Tullio A;Rouault-Pierre K;Abarrategi A;Mian S;Grey W;Gribben J;Stewart A;Blackwood E;Bonnet D
阿糖胞苷 (AraC) 是治疗 AML 最有效的单药。然而，克服 AML 中的 AraC 耐药性仍然是一个未得到满足的医疗需求。在这里，我们证明 CHK1 抑制剂 (CHK1i) GDC-0575 在体外和体内增强 AraC 介导的 AML 细胞杀伤，从而消除任何涉及 DNA 修复的潜在化疗耐药机制。重要的是，这种药物组合不会影响正常的长期造血干/祖细胞。此外，在 AraC 中添加 CHK1i 不会产生从头突变，并且在 AraC 具有诱变性的患者样本中，添加 CHK1i 似乎可以消除突变克隆的产生。最后，我们观察到持续残留的白血病细胞处于静止状态，当通过粒细胞集落刺激因子（G-CSF）给药强制进入周期时，可以对治疗产生反应。这种药物组合（AraC+CHK1i+G-CSF）将为在临床上更有效地治疗 AML 打开大门。克服 AML 中的阿糖胞苷耐药性仍然是一个未得到满足的医疗需求。在这里，作者表明，CHK1抑制剂GDC-0575与阿糖胞苷和G-CSF联合使用具有显着的抗白血病作用，并且对正常骨髓干细胞和祖细胞没有毒性。
Cytarabine (AraC) represents the most effective single agent treatment for AML. Nevertheless, overriding AraC resistance in AML remains an unmet medical need. Here we show that the CHK1 inhibitor (CHK1i) GDC-0575 enhances AraC-mediated killing of AML cells both in vitro and in vivo, thus abrogating any potential chemoresistance mechanisms involving DNA repair. Importantly, this combination of drugs does not affect normal long-term hematopoietic stem/progenitors. Moreover, the addition of CHK1i to AraC does not generate de novo mutations and in patients’ samples where AraC is mutagenic, addition of CHK1i appears to eliminate the generation of mutant clones. Finally, we observe that persistent residual leukemic cells are quiescent and can become responsive to the treatment when forced into cycle via granulocyte colony-stimulating factor (G-CSF) administration. This drug combination (AraC+CHK1i+G-CSF) will open the doors for a more efficient treatment of AML in the clinic. Overriding cytarabine resistance in AML remains an unmet medical need. Here, the authors show that the CHK1 inhibitor GDC-0575 in combination with cytarabine and G-CSF has a significant anti-leukemic effect without toxicity to normal marrow stem and progenitor cells.