Downregulation of c-Myc expression confers sensitivity to CHK1 inhibitors in hematologic malignancies

• 作者: Kai-long Jiang Le-xian Tong Tao Wang Han-lin Wang Xiao-bei Hu Gao-ya Xu Ting-ting Jin Wei-juan Kan Lei Xu Jia-nan Li Kai-xiang Zhang Ning Song Jie-yu Liu Meng-meng Zhang Wen-biao Wu Yu-qi Xiang An-hui Gao Yong-zhou Hu Yu-bo Zhou Tao Liu Jian-min Yang Jia Li
• 来源期刊: 中国药理学报（英文版）
• 年，卷（期）: 2022,（1）
• 所属期刊栏目: Cbemotherapy
• 页码范围: 220-228
• 页数: 9页
• 语种: 英文

摘要

Checkpoint kinase 1 inhibitors(CHK1 i)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.