Author:

Keywords:

kinase inhibitor, resistance, eosinophilia, oncogene, tyrosine kinase, idiopathic hypereosinophilic syndrome, gastrointestinal stromal tumor, imatinib mesylate therapy, chronic myeloid-leukemia, renal-cell carcinoma, myeloproliferative disease, molecular remission, tyrosine kinases, pdgfr-beta, Science & Technology, Life Sciences & Biomedicine, Oncology, Hematology, IMATINIB MESYLATE, KINASE INHIBITOR, MOLECULAR REMISSION, MYELOID-LEUKEMIA, TYROSINE KINASES, PDGFR-BETA, FUSION, RESISTANCE, DASATINIB, AMN107, Aged, Animals, Benzenesulfonates, Blast Crisis, Blotting, Western, Cells, Cultured, Chronic Disease, Drug Resistance, Neoplasm, Humans, Hypereosinophilic Syndrome, Male, Mice, Mutation, Niacinamide, Oncogene Proteins, Fusion, Phenylurea Compounds, Phosphorylation, Precursor Cells, B-Lymphoid, Protein Kinase Inhibitors, Pyridines, Receptor, Platelet-Derived Growth Factor alpha, Receptors, Vascular Endothelial Growth Factor, Salvage Therapy, Sorafenib, mRNA Cleavage and Polyadenylation Factors, 1103 Clinical Sciences, 1112 Oncology and Carcinogenesis, Immunology, 3201 Cardiovascular medicine and haematology, 3202 Clinical sciences, 3211 Oncology and carcinogenesis

Abstract:

Chronic eosinophilic leukemia (CEL) is a rare myeloproliferative neoplasm characterized by the FIP1L1-PDGFRA fusion gene, variant PDGFRA fusions or other genetic lesions. Most FIP1L1-PDGFRA positive patients enjoy durable and complete molecular responses to low-dose imatinib (Glivec/Gleevec). However, resistance mediated by a T674I mutation in the ATP-binding pocket of PDGFRA has been reported in advanced disease, and sorafenib, a potent inhibitor of RAF-1, B-RAF, VEGFR and PDGFR, is active against this mutant in vitro. We describe a case of FIP1L1-PDGFR alpha T674I CEL in blast crisis that responded to sorafenib (Nexavar). However, this clinical response was short-lived because of the rapid emergence of a FIP1L1-PDGFR alpha D842V mutant. An N-Nitroso-N-ethylurea-mutagenesis screen indeed identified this mutant as a major sorafenib-resistant mutant. In vitro, the novel FIP1L1-PDGFR alpha D842V mutant is highly resistant to sorafenib, imatinib, dasatinib (Sprycell) and PKC412 (Midostaurin). Thus, sorafenib is clinically active in imatinib-resistant FIP1L1-PDGFR alpha T674I CEL, but the rapid emergence of other mutants may limit the response duration. The identification of new PDGFR inhibitors will be required to overcome resistance by this D842V mutant. Leukemia (2009) 23, 845-851; doi:10.1038/leu. 2009.2; published online 12 February 2009