Abstract
The cells expressing the T674I point mutant of FIP1-like-1-platelet-derived growth factor receptor alpha (FIP1L1-PDGFRα) in hypereosinophilics syndrome (HES) are resistant to imatinib and some second-generation tyrosine kinase inhibitors (TKIs). There is a desperate need to develop therapy to combat this acquired drug resistance. DCC-2036 has been synthesized as a third-generation TKI to combat especially the Bcr-Abl T315I mutant in chronic myeloid leukemia. This study evaluated the effect of DCC-2036 on FIP1L1-PDGFRα-positive cells, including the wild type (WT) and the T674I mutant. The in vitro effects of DCC-2036 on the PDGFRα signal pathways, proliferation, cell cycling and apoptosis of FIP1L1-PDGFRα-positive cells were investigated, and a nude mouse xenograft model was employed to assess the in vivo antitumor activity. We found that DCC-2036 decreased the phosphorylated levels of PDGFRα and its downstream targets without apparent effects on total protein levels. DCC-2036 inhibited proliferation, and induced apoptosis with MEK-dependent up-regulation of the pro-apoptotic protein Bim in FIP1L1-PDGFRα-positive cells. DCC-2036 also exhibited in vivo antineoplastic activity against cells with T674I FIP1L1-PDGFRα. In summary, FIP1L1-PDGFRα-positive cells are sensitive to DCC-2036 regardless of their sensitivity to imatinib. DCC-2036 may be a potential compound to treat imatinib-resistant HES.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis / drug effects
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Apoptosis / genetics
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Apoptosis Regulatory Proteins / genetics
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Apoptosis Regulatory Proteins / metabolism
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Bcl-2-Like Protein 11
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Benzamides / pharmacology*
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Codon
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Disease Models, Animal
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Drug Resistance, Neoplasm / genetics*
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Gene Expression Regulation, Leukemic / drug effects
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Humans
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Imatinib Mesylate
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Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy
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Leukemia, Myelogenous, Chronic, BCR-ABL Positive / genetics
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Leukemia, Myelogenous, Chronic, BCR-ABL Positive / metabolism
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Leukemia, Myelogenous, Chronic, BCR-ABL Positive / pathology
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Membrane Proteins / genetics
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Membrane Proteins / metabolism
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Mice
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Mutation*
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Oncogene Proteins, Fusion / genetics*
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Phosphorylation
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Piperazines / pharmacology*
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Protein Kinase Inhibitors / pharmacology*
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism
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Pyrimidines / pharmacology*
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Quinolines / pharmacology*
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Receptor, Platelet-Derived Growth Factor alpha / genetics*
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Signal Transduction
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Tumor Burden
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Xenograft Model Antitumor Assays
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mRNA Cleavage and Polyadenylation Factors / genetics*
Substances
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Apoptosis Regulatory Proteins
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BCL2L11 protein, human
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Bcl-2-Like Protein 11
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Bcl2l11 protein, mouse
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Benzamides
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Codon
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DCC-2036
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Membrane Proteins
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Oncogene Proteins, Fusion
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Piperazines
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Protein Kinase Inhibitors
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Proto-Oncogene Proteins
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Pyrimidines
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Quinolines
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mRNA Cleavage and Polyadenylation Factors
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Imatinib Mesylate
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FIP1L1-PDGFRA fusion protein, human
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Receptor, Platelet-Derived Growth Factor alpha
Grants and funding
This research was supported by grants from the Research Foundation of Guangzhou Bureau of Science and Technology, China (grant to J. Pan), the National Natural Science Fund for Distinguished Young Scholars (no. 81025021 to J. Pan), the Research Foundation of Education Bureau of Guangdong Province, China (grant cxzd1103 to J. Pan), the National Basic Research Program of China (973 Program grant no.2009CB825506 to J. Pan), the National Hi-Tech Research and Development Program of China (863 Program grant no. 2008AA02Z420 to J. Pan), and the Fundamental Research Funds for the Central Universities (to J. Pan). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.