Purpose: The majority of gastrointestinal stromal tumors harbor mutations in the receptor tyrosine kinases KIT or platelet-derived growth factor receptor A (PDGFRA), and respond to treatment with the tyrosine kinase inhibitor imatinib. Some tumors, however, show primary resistance to imatinib treatment, and most others become resistant during treatment. The most common mechanism of imatinib resistance involves specific mutations in the kinase domains of KIT or PDGFRA. We tested the activity of SU11248, an orally active small-molecule tyrosine kinase inhibitor, to inhibit important imatinib-resistant KIT and PDGFRA mutants. Experimental Design: Primary imatinib-resistant tumor cells and cell lines expressing clinically identified imatinib-resistant KIT-V654A, KIT-T670I, or PDGFRA-D842V mutant isoforms were evaluated for sensitivity to SU11248 by Western immunoblotting and proliferation assays. Three patients with the KIT-V654A mutation were treated with SU11248. Results: Based on ex vivo assays, SU11248 potently inhibits KIT kinase activity of V654A and T670I mutants and suppresses proliferation of the cells expressing these mutations. Sensitivity of KIT-V654A and KIT-T670I mutants to SU11248 was confirmed using cell lines expressing these mutants. In contrast, SU11248 did not potently inhibit the PDGFRA-D842V mutant. In agreement with these results, two of the three imatinib-resistant patients with the KIT-V654A mutation responded to SU11248 treatment. Conclusions: These studies suggest that SU11248 may be a useful therapeutic agent to treat gastrointestinal stromal tumors harboring the imatinib-resistant KIT-V654A or KIT-T670I mutations, but it has no effect on the activity of the PDGFRA-D842V mutant. Specific kinase inhibitors should be designed to inhibit the constitutive activating PDGFRA mutation at codon 842.
Genetic abnormalities that result in expression of chimeric tyrosine kinase proteins such as BCR-ABL1 and ETV6-PDGFR are common causes of hematopoietic malignancies. The paradigm for constitutive activation of these fusion tyrosine kinases is enforced homodimerization by self-association domains present in the fusion partner proteins. The unique interstitial deletion on chromosome 4q12 that leads to expression of the FIP1L1-PDGFR␣ fusion tyrosine kinase was recently identified as a cause of chronic eosinophilic leukemia. In this report, we demonstrate that FIP1L1 is completely dispensable for PDGFR␣ activation in vitro and in vivo. Instead, truncation of PDGFR␣ between two conserved tryptophan residues in the juxtamembrane (JM) domain is required for kinase activation and transforming potential of FIP1L1-PDGFR␣. The presence of a complete JM domain in FIP1L1-PDGFR␣ is inhibitory, but this autoinhibition can be overcome by enforced homodimerization. Similar effects of the JM domain in the context of PDGFR were observed. These results suggest that disruption of the autoinhibitory JM domain is an alternative, dimerization-independent mechanism by which chimeric tyrosine kinases are constitutively activated and induce leukemogenesis.fusion gene ͉ leukemia ͉ oncogene ͉ tyrosine kinase P rotein tyrosine kinase genes are frequent targets of chromosomal rearrangements in hematopoietic malignancies and, to a minor extent, in some solid tumors (1, 2). As a consequence, such chromosomal abnormalities result in expression of fusion tyrosine kinases, in which the tyrosine kinase domains are fused in-frame to distinct N-terminal partner proteins that contain homotypic oligomerization domains. Homodimerization of the fusion tyrosine kinases by the N-terminal oligomerization domains leads to autophosphorylation at tyrosine residues and constitutive kinase activation, as well as activation of critical downstream signaling effectors that induce cellular proliferation (1). Well studied examples include BCR-ABL, ETV6-PDGFRB, ZNF198-FGFR1, and NPM-ALK, in which the presence of the oligomerization domains of the fusion partners have been shown to be indispensable for kinase activation and for transforming properties of the fusion proteins (2-6).FIP1L1-PDGFRA is a fusion gene that has been identified in patients with hypereosinophilic syndrome͞chronic eosinophilic leukemia (CEL) and systemic mast cell disease (7,8). FIP1L1 is fused to PDGFRA due to an interstitial deletion on chromosome 4q12, in contrast to other fusion tyrosine kinases that are typically generated by chromosomal translocations (7-13). We and others have shown that the FIP1L1-PDGFR␣ fusion protein is a constitutively activated tyrosine kinase that confers growth factor-independent growth to hematopoietic cells and is sensitive to inhibition by imatinib (7,12,14). FIP1L1 is a protein involved in polyadenylation, but it is unknown whether FIP1L1 confers dimerization properties, because it does not harbor any known protein-protein interaction domains (15).Interestingly...
The FIP1L1-PDGFRA oncogene is a common cause of chronic eosinophilic leukemia (CEL), and encodes an activated tyrosine kinase that is inhibited by imatinib. FIP1L1-PDGFRA-positive patients with CEL respond to low-dose imatinib therapy, but resistance due to acquired T674I mutation has been observed. We report here the identification of sorafenib as a potent inhibitor of the FIP1 like 1-platelet-derived growth
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