Cyclin-dependent kinase 7/9 inhibitor SNS-032 abrogates FIP1-like-1 platelet-derived growth factor receptor α and bcr-abl oncogene addiction in malignant hematologic cells
Purpose: The “gate-keeper” mutations T674I platelet-derived growth factor receptor a (PDGFRa) in hypereosinophilic syndrome (HES) and T315I Bcr-Abl in chronic myeloid leukemia (CML) are resistant against imatinib and also the second-generation small-molecule tyrosine kinase inhibitors (TKI). However, to combat acquired potential to deal with imatinib, an alternate approach would be to reduce the expression from the addicted gene to efficiently kill resistant malignant hematologic cells. The objective of this research ended up being to assess the technique of shutting lower the transcription and expression of FIP1-like-1 (FIP1L1)-PDGFRa and Bcr-Abl with SNS-032, an inhibitor of cyclin-dependent kinase 7 (CDK7) and CDK9 in phase I numerous studies.
Experimental design: The results of SNS-032 on PDGFRa and Bcr-Abl signaling pathways, apoptosis, and cell cycling were examined in TKI-resistant cells of HES and CML. The in vivo antitumor activity of SNS-032 was assessed with xenografted BaF3-T674I FIP1L1-PDGFRa and KBM5-T315I Bcr-Abl cells in nude mouse models.
Results: SNS-032 inhibited the phosphorylation on Ser5 and Ser2 BMS-387032 of RNA polymerase II. SNS-032 decreased both mRNA and protein amounts of FIP1L1-PDGFRa and Bcr-Abl and inhibited the proliferation of malignant cells expressing FIP1L1-PDGFRa or Bcr-Abl. Additionally, it decreased the phosphorylation of downstream molecules. It caused apoptosis by triggering both mitochondrial path and also the dying receptor path.
Conclusions: This CDK7/9 inhibitor potently inhibits FIP1L1-PDGFRa-positive HES cells and Bcr-Abl-positive CML cells no matter their sensitivity to imatinib. SNS-032 might have potential for hematologic malignancy by abrogating oncogene addiction.