Dasatinib in Imatinib-Resistant Philadelphia Chromosome–Positive Leukemias

Talpaz, Moshe; Shah, Neil P.; Kantarjian, Hagop M.; Donato, Nicholas J.; Nicoll, John; Paquette, Ron; Cortes, Jorge; O’Brien, Susan; Nicaise, Claude; Bleickardt, Eric; Blackwood-Chirchir, M. Anne; Iyer, Vishwanath R.; Chen, Tai-Tsang; Huang, Fei; DeCillis, Arthur P.; Sawyers, Charles L.

doi:10.1056/nejmoa055229

Cited by 1,580 publications

(1,264 citation statements)

References 30 publications

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“…Dasatinib is the second generation tyrosine kinase inhibitor that can bind both inactive and active forms of BCR/ABL [34]. Despite the fact that dasatinib is much more effective than imatinib for the treatment of CML, resistance to dasatinib is still the major drawback in CML treatment [35].…”

Section: Discussionmentioning

confidence: 99%

A novel mechanism of dasatinib-induced apoptosis in chronic myeloid leukemia; ceramide synthase and ceramide clearance genes

et al. 2011

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Sphingolipids are bioeffector molecules that control various aspects of cell growth, proliferation, apoptosis, and drug resistance. Ceramides, the central molecule of sphingolipid metabolism, are inducer of apoptosis and inhibitors of proliferation. Sphingosine-1-phosphate (S1P) and glucosyleceramide, converted from ceramides by sphingosine kinase-1 (SK-1) and glucosyleceramide synthase (GCS) enzymes, respectively, inhibit apoptosis and develop resistance to chemotherapeutic drugs. In this study, we examined the therapeutic potentials of bioactive sphingolipids in chronic myeloid leukemia (CML) alone and in combination with dasatinib in addition to investigate the roles of ceramide-metabolizing genes in dasatinib-induced apoptosis. Cytotoxic effects of dasatinib, C8:ceramide, PDMP, and SK-1 inhibitor were determined by XTT cell proliferation assay. Changes in caspase-3 enzyme activity and mitochondrial membrane potential (MMP) were measured using caspase-3 colorimetric assay and JC-1 MMP detection kit. Expression levels of ceramide-metabolizing genes were examined by qRT-PCR. Application of ceramide analogs and inhibitors of ceramide clearance genes decreased cell proliferation and induced apoptosis. Targeting bioactive sphingolipids towards generation/accumulation of ceramides increased apoptotic effects of dasatinib, synergistically. It was shown for the first time that dasatinib induces apoptosis through downregulating expression levels of antiapoptotic SK-1 but not GCS, and upregulating expression levels of ceramide synthase (CerS) genes, especially CerS1, in K562 cells. On the other hand, dasatinib downregulates expression levels of both GCS and SK-1 and upregulate apoptotic CerS2, −5 and −6 genes in Meg-01 cells. Increasing endogenous ceramide levels and decreasing prosurvival lipids, S1P, and GC, can open the way of more effective treatment of CML.

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Section: Discussionmentioning

confidence: 99%

A novel mechanism of dasatinib-induced apoptosis in chronic myeloid leukemia; ceramide synthase and ceramide clearance genes

et al. 2011

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“…In addition to inhibiting ABL, ARG, PDGFRα, PDGFRβ and KIT, dasatinib is a potent inhibitor of all Src family kinases 41 . Both dasatinib and nilotinib are active against some imatinib-resistant BCR-ABL mutants, and dasatinib was recently approved by the FDA for treatment of imatinib-refractory CML and Ph + ALL 42 . In CML cells, BCR-ABL activates various signalling pathways, including Ras-Raf-MAPK, PI3K-Akt and signal transducer and activator of transcription 5 (STAT5).…”

Section: Abl Inhibitors: Imatinib Dasatinib and Nilotinibmentioning

confidence: 99%

Molecular mechanisms of cardiotoxicity of tyrosine kinase inhibition

2007

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“…Although new phase 1 clinical trials with the dual Src/Abl inhibitor dasatinib (BMS-354825) and the selective Abl inhibitor AMN107 show encouraging results (O'Hare et al, 2005), as they suppress the activity of most BCR/ABL mutants (except T315I) (O'Hare et al, 2005), in vitro evidence suggests that resistance to these new compounds may develop through mechanisms involving the selection and expansion of BCR/ABL þ cell clones carrying the T315I BCR/ABL mutant (Deininger et al, 2005b). Additionally, dasatinib, like imatinib, is not effective in the treatment of CML-BC patients (Talpaz et al, 2006), and in killing the most primitive quiescent CML cells (Copland et al, 2006) and, therefore, it may also be ineffective in preventing disease progression.…”

Section: CML Bcr/abl and Imatinibmentioning

confidence: 99%

ReSETting PP2A tumour suppressor activity in blast crisis and imatinib-resistant chronic myelogenous leukaemia

Perrotti

Neviani

2006

Br J Cancer

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The deregulated kinase activity of p210-BCR/ABL oncoproteins, hallmark of chronic myelogenous leukaemia (CML), induces and sustains the leukaemic phenotype, and contributes to disease progression. Imatinib mesylate, a BCR/ABL kinase inhibitor, is effective in most of chronic phase CML patients. However, a significant percentage of CML patients develop resistance to imatinib and/or still progresses to blast crisis, a disease stage that is often refractory to imatinib therapy. Furthermore, there is compelling evidence indicating that the CML leukaemia stem cell is also resistant to imatinib. Thus, there is still a need for new drugs that, if combined with imatinib, will decrease the rate of relapse, fully overcome imatinib resistance and prevent blastic transformation of CML. We recently reported that the activity of the tumour suppressor protein phosphatase 2A (PP2A) is markedly inhibited in blast crisis CML patient cells and that molecular or pharmacologic re-activation of PP2A phosphatase led to growth suppression, enhanced apoptosis, impaired clonogenic potential and decreased in vivo leukaemogenesis of imatinib-sensitive and -resistant (T315I included) CML-BC patient cells and/or BCR/ABL þ myeloid progenitor cell lines. Thus, the combination of PP2A phosphatase-activating and BCR/ABL kinase-inhibiting drugs may represent a powerful therapeutic strategy for blast crisis CML patients.

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Dasatinib in Imatinib-Resistant Philadelphia Chromosome–Positive Leukemias

Abstract: Dasatinib induces hematologic and cytogenetic responses in patients with CML or Ph-positive ALL who cannot tolerate or are resistant to imatinib. (ClinicalTrials.gov number, NCT00064233 [ClinicalTrials.gov].).

Cited by 1,580 publications

References 30 publications

A novel mechanism of dasatinib-induced apoptosis in chronic myeloid leukemia; ceramide synthase and ceramide clearance genes

A novel mechanism of dasatinib-induced apoptosis in chronic myeloid leukemia; ceramide synthase and ceramide clearance genes

Molecular mechanisms of cardiotoxicity of tyrosine kinase inhibition

ReSETting PP2A tumour suppressor activity in blast crisis and imatinib-resistant chronic myelogenous leukaemia

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