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.
    Leukemia & lymphoma 02/2008; 49(1):19-26. DOI:10.1080/10428190701713689 · 2.89 Impact Factor
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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.
    Nuclear Medicine and Biology 06/2005; 32(4):313-21. DOI:10.1016/j.nucmedbio.2005.01.008 · 2.41 Impact Factor
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    • "utility of Src inhibition will continue to expand. At this writing, two clinical trials continue to investigate Src inhibition in imatinib mesylate (Gleevec, Novartis) resistant CML patients, and recent studies have shown the effectiveness of combination agents that target both Bcr-Abl and Src in imatinib mesylate resistant CML cell lines [8] [9]. Because Src activation is frequent in a variety of tumors, occurring most often during tumor progression, it is almost certain that Src inhibitors will reach clinical trials for therapy of late stage solid tumors such as colon, prostate and pancreatic, solid tumors in which new therapies are desperately needed. "
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    ABSTRACT: Despite its discovery nearly a century ago, the functions of the Src family of protein tyrosine kinases (SFKs) remain incompletely understood. While much has been learned regarding the functions of Src family kinases in the last few years, new roles for Src, particularly in promoting the progression of cancer towards the metastatic phenotype, continue to emerge. SFKs, through their functions as kinases and adapter proteins in signaling complexes, regulate such diverse cellular events as proliferation, migration, cell cycle control, and apoptosis. In tumor cells, the kinase activity of Src is frequently activated, with greater increases during progressive stages. Likewise, resistance to chemotherapy also corresponds with Src kinase activity. Thus, Src activation is predictive of poor prognosis in several tumors. Recently, selective SFK inhibitors are showing promise in clinical trials in imatinib mesylate (Gleevec, Novartis) resistant chronic myelogenous leukemia. However, in vitro studies have suggested that Src inhibitors may hold promise in the treatment of solid tumors such as colon and pancreatic cancer in which new therapeutic inhibitors are desperately needed. This review will summarize briefly the structure and function of Src and the evidence for Src in promoting tumor progression and metastasis. As recent work in this laboratory and others has demonstrated that Src is a regulator of expression of diverse pro-angiogenic factors produced by tumor cells, and a regulator of the endothelial cells that respond to these factors, this review will focus on the role of Src in angiogenesis and potential roles of Src inhibitors as antiangiogenic agents.
    Current Cancer Therapy Reviews 12/2004; 1(1):45-50. DOI:10.2174/1573394052952500
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