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

Clin Cancer Res. 2012 Apr 1;18(7):1966-78. doi: 10.1158/1078-0432.CCR-11-1971. Epub 2012 Mar 23.

Abstract

Purpose: The "gate-keeper" mutations T674I platelet-derived growth factor receptor α (PDGFRα) in hypereosinophilic syndrome (HES) and T315I Bcr-Abl in chronic myeloid leukemia (CML) are resistant to imatinib and the second-generation small-molecule tyrosine kinase inhibitors (TKI). 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 (FIP1L1)-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-Abl 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-T674I FIP1L1-PDGFRα and KBM5-T315I 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 and inhibited the proliferation of malignant cells expressing FIP1L1-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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Blotting, Western
  • Cell Cycle / drug effects
  • Cell Line
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cyclin-Dependent Kinase 9 / antagonists & inhibitors
  • Cyclin-Dependent Kinase 9 / metabolism
  • Cyclin-Dependent Kinase-Activating Kinase
  • Cyclin-Dependent Kinases / antagonists & inhibitors
  • Cyclin-Dependent Kinases / metabolism
  • Female
  • Fusion Proteins, bcr-abl / antagonists & inhibitors*
  • Fusion Proteins, bcr-abl / genetics
  • Fusion Proteins, bcr-abl / metabolism
  • Humans
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy*
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / genetics
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / metabolism
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Oncogene Proteins, Fusion / antagonists & inhibitors*
  • Oncogene Proteins, Fusion / genetics
  • Oncogene Proteins, Fusion / metabolism
  • Oxazoles / pharmacology*
  • Phosphorylation / drug effects
  • Receptor, Platelet-Derived Growth Factor alpha / antagonists & inhibitors*
  • Receptor, Platelet-Derived Growth Factor alpha / genetics
  • Receptor, Platelet-Derived Growth Factor alpha / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction / drug effects
  • Thiazoles / pharmacology*
  • Xenograft Model Antitumor Assays
  • mRNA Cleavage and Polyadenylation Factors / antagonists & inhibitors*
  • mRNA Cleavage and Polyadenylation Factors / genetics
  • mRNA Cleavage and Polyadenylation Factors / metabolism

Substances

  • N-(5-(((5-(1,1-dimethylethyl)-2-oxazolyl)methyl)thio)-2-thiazolyl)-4-piperidinecarboxamide
  • Oncogene Proteins, Fusion
  • Oxazoles
  • Thiazoles
  • mRNA Cleavage and Polyadenylation Factors
  • FIP1L1-PDGFRA fusion protein, human
  • Receptor, Platelet-Derived Growth Factor alpha
  • Fusion Proteins, bcr-abl
  • Cyclin-Dependent Kinase 9
  • Cyclin-Dependent Kinases
  • Cyclin-Dependent Kinase-Activating Kinase