Efficacy of dual-specific Bcr-Abl and Src-family kinase inhibitors in cells sensitive and resistant to imatinib mesylate

Department of Haematology, Imperial College London, Hammersmith Hospital, London, UK.
Leukemia (Impact Factor: 10.43). 09/2004; 18(8):1352-6. DOI: 10.1038/sj.leu.2403416
Source: PubMed


Monotherapy of chronic myeloid leukemia (CML) with imatinib mesylate has been cast into shadow by the evolution of clinical resistance during therapy. Resistance to imatinib can arise by multiple mechanisms including amplification or mutation of Bcr-Abl, and continuity of imatinib therapy is probably a poor option for either of these patient groups. Recently, however, a structurally distinct new class of drugs, the pyrido[2,3-d]pyrimidines, has been described, and these compounds are predicted to make different molecular contacts in the Abl kinase domain. These drugs potently target both the Bcr-Abl and Src-family kinase activities, both of which are thought to be relevant to survival of the leukemic cell. We asked whether these drugs could selectively induce cell death in murine cell line models of CML cells sensitive and resistant to imatinib by different mechanisms. We show that whereas the pyrido[2,3-d] pyrimidines are indeed highly potent in suppressing proliferation of Bcr-Abl-overexpressing imatinib-resistant cells, they are almost completely ineffective against cells expressing the T315I mutant. This implies that despite structural differences from imatinib, these drugs are unlikely to be useful in patients expressing this mutant Bcr-Abl protein, but may be effective in cases where selection of cells overexpressing the oncoprotein leads to refractoriness to imatinib.

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Available from: François-Xavier Mahon, Sep 25, 2014
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    • "As discussed above, preclinical studies have demonstrated that pharmacologic or genetic inhibition of SFKs induces apoptosis and growth arrest in BCR-ABL transformed cells [20,23 – 25,48] and may overcome imatinib resistance [22,40,64]. Moreover, dual inhibitors of BCR-ABL and SFKs may be less susceptible to conformational resistance than imati-nib [65]. "
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    ABSTRACT: The BCR-ABL kinase inhibitor imatinib has shown significant efficacy in chronic myeloid leukemia (CML) and is the standard front-line therapy for patients in chronic phase. However, a substantial number of patients are either primarily refractory or acquire resistance to imatinib. While a number of mechanisms are known to confer resistance to imatinib, increasing evidence has demonstrated a role for BCR-ABL-independent pathways. The Src-family kinases (SFKs) are one such pathway and have been implicated in imatinib resistance. Additionally, these kinases are key to the progression of CML and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). The dual SFK/BCR-ABL inhibitor dasatinib is now clinically available and has markedly greater potency compared with imatinib against native BCR-ABL and the majority of imatinib-resistant BCR-ABL mutants. Therefore, this agent, as well as other dual SFK/BCR-ABL inhibitors under development, could provide added therapeutic advantages by overcoming both BCR-ABL-dependent (i.e. BCR-ABL mutations) and -independent forms of imatinib resistance and delaying transition to advanced phase disease. In this review, we discuss the preclinical and clinical evidence demonstrating the involvement of SFKs in imatinib resistance and the progression of CML and Ph+ ALL, as well as the potential role of dual SFK/BCR-ABL inhibition in the management of these diseases.
    Full-text · Article · Feb 2008 · Leukemia & lymphoma
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    • "phosphorylation of b-catenin b-Catenin is a target for several members of the Src family tyrosine kinase (Piedra et al, 2001; Coluccia et al, 2006), which are known to contribute to Bcr-Abl þ leukemogenesis (Tipping et al, 2004). Therefore, b-catenin might be phosphorylated by either Bcr-Abl itself and/or its proximal Src effectors in human CML cells. "
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    ABSTRACT: Self-renewal of Bcr-Abl(+) chronic myeloid leukemia (CML) cells is sustained by a nuclear activated serine/threonine-(S/T) unphosphorylated beta-catenin. Although beta-catenin can be tyrosine (Y)-phosphorylated, the occurrence and biological relevance of this covalent modification in Bcr-Abl-associated leukemogenesis is unknown. Here we show that Bcr-Abl levels control the degree of beta-catenin protein stabilization by affecting its Y/S/T-phospho content in CML cells. Bcr-Abl physically interacts with beta-catenin, and its oncogenic tyrosine kinase activity is required to phosphorylate beta-catenin at Y86 and Y654 residues. This Y-phospho beta-catenin binds to the TCF4 transcription factor, thus representing a transcriptionally active pool. Imatinib, a Bcr-Abl antagonist, impairs the beta-catenin/TCF-related transcription causing a rapid cytosolic retention of Y-unphosphorylated beta-catenin, which presents an increased binding affinity for the Axin/GSK3beta complex. Although Bcr-Abl does not affect GSK3beta autophosphorylation, it prevents, through its effect on beta-catenin Y phosphorylation, Axin/GSK3beta binding to beta-catenin and its subsequent S/T phosphorylation. Silencing of beta-catenin by small interfering RNA inhibited proliferation and clonogenicity of Bcr-Abl(+) CML cells, in synergism with Imatinib. These findings indicate the Bcr-Abl triggered Y phosphorylation of beta-catenin as a new mechanism responsible for its protein stabilization and nuclear signalling activation in CML.
    Full-text · Article · Apr 2007 · The EMBO Journal
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    • "The appearance of resistance to Gleevec therapy [10] has spurred the development of additional Bcr–Abl inhibitors, which include the pyridopyrimidinones. Many of these secondgeneration drug candidates are significantly more potent than Gleevec, are effective in Gleevec-resistant cell lines [11] [12] [13] [14] [15] [16] and — two in particular, AMN107 [17] and BMS354825 [18] —are showing promise in clinical trials for patients who have failed Gleevec. In fact, these compounds are generally less target specific compared with Gleevec, but they owe their increased overall potency and efficacy in Gleevecresistant CML to concomitant inhibition of multiple signaling pathways (i.e., Abl and Src family kinases) [16]. "
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    ABSTRACT: The pyridopyrimidinones are a potent class of inhibitors of c-Abl kinase and Bcr-Abl kinase, the causative fusion protein in chronic myelogenous leukemia and Src family kinases. A novel method for routine, high-yield no-carrier-added synthesis of [(124)I]-, [(125)I]- and [(131)I]-6-(2,6-dichlorophenyl)-2-(4-iodophenylamino)-8-methyl-8H-pyrido[2,3-d]pyrimidin-7-one has been developed. The 4'-trimethylstannyl- or 4'-tri-n-butylstannyl-pyridopyrimidinone precursors were prepared from the aryl bromide via a palladium-mediated coupling with hexaalkylditin (dioxane/microwave irradiation/10 min at 160 degrees C). The radioiodination of 4'-stannylpyridopyrimidinones was found to optimally occur via an iododestannylation with Na(124)I, Na(125)I or Na(131)I in the presence of an oxidant [30% H(2)O(2)/HOAc (1:3)/10 min] in 79-87% radiochemical yield with >99% radiochemical purity. The total radiosynthesis time was 30 min. The 4-iodophenylpyridopyrimidinone 2 inhibited recombinant Abl kinase activity with an IC(50) of 2.0 nM. Cell proliferation of K562 and A431 cells was inhibited with an IC(50) of 2.0 and 20 nM, respectively. Rapid cellular uptake and equilibrium were observed within 10-15 min using [(131)I]-4-iodophenylpyridopyrimidinone 6c in K562 and A431 cells and demonstrated a 2.8-fold uptake selectivity for the Bcr-Abl-expressing K562 cells at 60 min. These results suggest that pyridopyrimidinone radiotracers may be useful in imaging Abl-, Bcr-Abl- or Src-expressing malignancies.
    Full-text · Article · Jun 2005 · Nuclear Medicine and Biology
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