Antitumor activity of S116836, a novel tyrosine kinase inhibitor, against imatinib-resistant FIP1L1-PDGFRα-expressing cells

Oncotarget. 2014 Nov 15;5(21):10407-20. doi: 10.18632/oncotarget.2090.

Abstract

The FIP1-like-1-platelet-derived growth factor receptor alpha (FIP1L1-PDGFRα) fusion oncogene is the driver factor in a subset of patients with hypereosinophilic syndrome (HES)/chronic eosinophilic leukemia (CEL). Most FIP1L1-PDGFRα-positive patients respond well to the tyrosine kinase inhibitor (TKI) imatinib. Resistance to imatinib in HES/CEL has been described mainly due to the T674I mutation in FIP1L1-PDGFRα, which is homologous to the imatinib-resistant T315I mutation in BCR-ABL. Development of novel TKIs is imperative to overcome resistance to imatinib. We synthesized S116836, a novel TKI. In this study, we evaluated the antitumor activity of S116836 in FIP1L1-PDGFRα-expressing cells. The results showed that S116836 potently inhibited PDGFRα and its downstream signaling molecules such as STAT3, AKT, and Erk1/2. S116836 effectively inhibited the growth of the WT and T674I FIP1L1-PDGFRα-expressing neoplastic cells in vitro and in nude mouse xenografts. Moreover, S116836 induced intrinsic pathway of apoptosis as well as the death receptor pathway, coincided with up-regulation of the proapoptotic BH3-only protein Bim-EL through the Erk1/2 pathway. In conclusion, S116836 is active against WT and T674I FIP1L1-PDGFRα-expressing cells, and may be a prospective agent for the treatment of HES/CEL.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / administration & dosage*
  • Antineoplastic Agents / chemical synthesis
  • Apoptosis / drug effects
  • Apoptosis Regulatory Proteins / genetics
  • Apoptosis Regulatory Proteins / metabolism
  • Bcl-2-Like Protein 11
  • Benzamides / administration & dosage*
  • Benzamides / chemical synthesis
  • Benzamides / therapeutic use*
  • Cell Growth Processes / drug effects
  • Drug Resistance / genetics
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Hypereosinophilic Syndrome / drug therapy*
  • Imatinib Mesylate
  • Leukemia
  • Male
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Mutation / genetics
  • Oncogene Protein v-akt / metabolism
  • Oncogene Proteins, Fusion / genetics
  • Piperazines / therapeutic use*
  • Protein Kinase Inhibitors / administration & dosage*
  • Protein Kinase Inhibitors / chemical synthesis
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism
  • Pyrimidines / administration & dosage*
  • Pyrimidines / chemical synthesis
  • Pyrimidines / therapeutic use*
  • Receptor, Platelet-Derived Growth Factor alpha / genetics
  • Receptor, Platelet-Derived Growth Factor alpha / metabolism*
  • STAT3 Transcription Factor / metabolism
  • Signal Transduction / drug effects
  • Xenograft Model Antitumor Assays
  • mRNA Cleavage and Polyadenylation Factors / genetics
  • mRNA Cleavage and Polyadenylation Factors / metabolism*

Substances

  • Antineoplastic Agents
  • Apoptosis Regulatory Proteins
  • BCL2L11 protein, human
  • Bcl-2-Like Protein 11
  • Bcl2l11 protein, mouse
  • Benzamides
  • FIP1L1 protein, human
  • Membrane Proteins
  • Oncogene Proteins, Fusion
  • Piperazines
  • Protein Kinase Inhibitors
  • Proto-Oncogene Proteins
  • Pyrimidines
  • S116836
  • STAT3 Transcription Factor
  • mRNA Cleavage and Polyadenylation Factors
  • Imatinib Mesylate
  • Receptor, Platelet-Derived Growth Factor alpha
  • Oncogene Protein v-akt

Supplementary concepts

  • Pdgfra-Associated Chronic Eosinophilic Leukemia