髓系白血病
生物
白血病
细胞凋亡
细胞周期
DNA损伤
分子生物学
细胞周期检查点
细胞生长
作者
Kailong Jiang,Tong Lexian,Tao Wang,Han‐lin Wang,Hu Xiaobei,Xu Gaoya,Tingting Jin,Kan Weijuan,Lei Xu,Jia-Nan Li,Kaixiang Zhang,Ning Song,Liu Jieyu,Zhang Mengmeng,Wen-Biao Wu,Yu-qi Xiang,Anhui Gao,Yongzhou Hu,Yubo Zhou,Tao Liu,Jian-Min Yang,Jia Li
出处
期刊:Acta Pharmacologica Sinica
日期:2021-03-29
卷期号:: 1-9
被引量:1
标识
DOI:10.1038/s41401-021-00652-1
摘要
Checkpoint kinase 1 inhibitors (CHK1i) have shown impressive single-agent efficacy in treatment of certain tumors, as monotherapy or potentiators of chemotherapy in clinical trials, but the sensitive tumor types and downstream effectors to dictate the therapeutic responses to CHK1i remains unclear. In this study we first analyzed GDSC (Genomics of Drug Sensitivity in Cancer) and DepMap database and disclosed that hematologic malignancies (HMs) were relatively sensitive to CHK1i or CHK1 knockdown. This notion was confirmed by examining PY34, a new and potent in-house selective CHK1i, which exhibited potent anti-HM effect in vitro and in vivo, as single agent. We demonstrated that the downregulation of c-Myc and its signaling pathway was the common transcriptomic profiling response of sensitive HM cell lines to PY34, whereas overexpressing c-Myc could partially rescue the anticancer effect of PY34. Strikingly, we revealed the significant correlations between downregulation of c-Myc and cell sensitivity to PY34 in 17 HM cell lines and 39 patient-derived cell (PDC) samples. Thus, our results demonstrate that HMs are more sensitive to CHK1i than solid tumors, and c-Myc downregulation could represent the CHK1i efficacy in HMs.
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