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

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.

• Authors: Yingying Shen, Xiaomei Ren, Ke Ding, Zhang Zhang, Deping Wang, Jingxuan Pan
• Journal: Oncotarget (Oncotarget) Vol. 5 Issue 21 Pg. 10407-20 (Nov 15 2014) ISSN: 1949-2553 [Electronic] United States
• PMID: 25431951 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 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

Topics

• Animals
• Antineoplastic Agents (administration & dosage, chemical synthesis)
• Apoptosis (drug effects)
• Apoptosis Regulatory Proteins (genetics, metabolism)
• Bcl-2-Like Protein 11
• Benzamides (administration & dosage, chemical synthesis, 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, 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, chemical synthesis)
• Proto-Oncogene Proteins (genetics, metabolism)
• Pyrimidines (administration & dosage, chemical synthesis, therapeutic use)
• Receptor, Platelet-Derived Growth Factor alpha (genetics, metabolism)
• STAT3 Transcription Factor (metabolism)
• Signal Transduction (drug effects)
• Xenograft Model Antitumor Assays
• mRNA Cleavage and Polyadenylation Factors (genetics, metabolism)