Cyclin-dependent kinase 7/9 inhibitor SNS-032 abrogates FIP1-like-1 platelet-derived growth factor α and Bcr-Abl oncogene addiction in malignant hematologic cells
Purpose:The ”gate-keeper” mutations T6741 PDGFRα in hypereosinophilic syndrome (HES) and T3151 Bcr-Abl in chronic myeloid leukemia (CML),are resistant to imatinib and the second-generation small molecule tyrosine kinase inhibitors (TKIs).However,to combat acquired resistance to imatinib,an alternative approach is to decrease the expression of the addicted gene to efficiently kill resistant malignant hematologic cells.The purpose of this study was to evaluate the strategy of shutting down the transcription and expression of FIP1-like-1 (FIPIL1)-platelet derived growth factor receptor α (FIP1 L1-PDGFRα) and Bcr-Abl with SNS-032,an inhibitor of cyclin-dependent kinase 7 (CDK7) and CDK9 in phase Ⅰ clinical trials.Experimental Design:The effects of SNS-032 on PDGFRα and Bcr-Ab1 signaling pathways,apoptosis and cell cycling were analyzed in TKI-resistant cells of HES and CML.The in vivo antitumor activity of SNS-032 was assessed with xenografted BaF3-T6741 F1P1L1-PDGFRα and KBM5-T3151 Bcr-Abl cells in nude mouse models.Results:SNS-032 inhibited the phosphorylation on Ser5 and Ser2 of RNA polymerase Ⅱ.SNS-032 decreased both the mRNA and protein levels of FIP1L1-PDGFRα and Bcr-Abl,inhibited the proliferation of malignant cells expressing F1P1L1-PDGFRα or Bcr-Abl.It also decreased the phosphorylation of downstream molecules.It induced apoptosis by triggering both the mitochondrial pathway and the death receptor pathway.Conclusions:This CDK7/9 inhibitor potently inhibits FIP1L1-PDGFRα-positive HES cells and Bcr-Abl-positive CML cells regardless of their sensitivity to imatinib.SNS-032 may have potential in treating hematologic malignancy by abrogating oncogene addiction.
Yongbin Wu Bei Jin Xianping Shi Xiaoyong Sun Ke Ding Jingxuan Pan
Department of Pathophysiology,Zhongshan School of Medicine,Sun Yat-sen University,Guangzhou,China Key Laboratory of Regenerative Biology and Institute of Chemical Biology,Guangzhou Institute of Biom
国内会议
2012医学科学前沿暨第二届个体化治疗与抗肿瘤药物研究新趋向研讨会
深圳
英文
372-398
2012-07-13（万方平台首次上网日期，不代表论文的发表时间）