A novel molecular mechanism of primary resistance to FLT3-kinase inhibitors in AML

Breitenbuecher, Frank; Markova, Boyka; Kasper, Stefan; Carius, Birgit; Stauder, Torsten; Böhmer, Frank D.; Masson, Kristina; Rönnstrand, Lars; Huber, Christoph; Kindler, Thomas; Fischer, Thomas

doi:10.1182/blood-2007-11-126664

Cited by 110 publications

(101 citation statements)

References 36 publications

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“…Under nonapoptotic conditions Bim has been found to be sequestered by Mcl-1, which neutralizes its apoptotic activity. 37 In line with our results, it has been demonstrated that Noxa displaces Bim from sequestration by Mcl-1 in a mutually exclusive manner. 38,39 FI-700 reduces Mcl-1 by proteasome-mediated degradation in FLT3/ITD AML cells, which would result in the reduced ability of Mcl-1 to sequester proapoptotic Bim and facilitate Bim-dependent apoptosis.…”

Section: Discussionsupporting

confidence: 81%

“…It has been reported that a proportion of patients harboring FLT3 mutations exhibit primary resistance to FLT3 inhibitor treatment, although the precise mechanisms are largely unknown. 37,44 In our series, AML cells from one of the FLT3/ITD cases (case 11) showed resistance to FI-700-induced apoptosis. Of particular interest is whether the combined FLT3 inhibition and p53 activation could overcome specific mechanisms of resistance to FLT3 inhibitors.…”

Section: Discussionmentioning

confidence: 99%

“…The idea that Mcl-1 is a critical therapeutic target in FLT3/ITD AML is supported by the recent paper identifying a molecular mechanism leading to primary clinical resistance to the FLT3 inhibitor PKC412. 37 In that scenario, selection of a drug-resistant leukemic clone with atypical ITD mutation (FLT3_ITD627E) occurs upon start of treatment and the Mcl-1 levels become no longer suppressed by PKC412 treatment. We propose that the avid binding of Bim and Noxa to Mcl-1 could contribute to the synergistic apoptotic effect of the FI-700/ Nutlin-3 combination.…”

Section: Discussionmentioning

confidence: 99%

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Selective FLT3 inhibitor FI-700 neutralizes Mcl-1 and enhances p53-mediated apoptosis in AML cells with activating mutations of FLT3 through Mcl-1/Noxa axis

et al. 2009

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Treatment using Fms-like tyrosine kinase-3 (FLT3) inhibitors is a promising approach to overcome the dismal prognosis of acute myeloid leukemia (AML) with activating FLT3 mutations. Current trials are combining FLT3 inhibitors with p53-activating conventional chemotherapy. The mechanisms of cytotoxicity of FLT3 inhibitors are poorly understood. We investigated the interaction of FLT3 and p53 pathways after their simultaneous blockade using the selective FLT3 inhibitor FI-700 and the MDM2 inhibitor Nutlin-3 in AML. We found that FI-700 immediately reduced antiapoptotic Mcl-1 levels and enhanced Nutlininduced p53-mediated mitochondrial apoptosis in FLT3/internal tandem duplication cells through the Mcl-1/Noxa axis. FI-700 induced proteasome-mediated degradation of Mcl-1, resulting in the reduced ability of Mcl-1 to sequester proapoptotic Bim. Nutlin-3 induced Noxa, which displaced Bim from Mcl-1. The FI-700/Nutlin-3 combination profoundly activated Bax and induced apoptosis. Our findings suggest that FI-700 actively enhances p53 signaling toward mitochondrial apoptosis and that a combination strategy aimed at inhibiting FLT3 and activating p53 signaling could potentially be effective in AML.

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Section: Discussionsupporting

confidence: 81%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Selective FLT3 inhibitor FI-700 neutralizes Mcl-1 and enhances p53-mediated apoptosis in AML cells with activating mutations of FLT3 through Mcl-1/Noxa axis

et al. 2009

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“…Interestingly, during the preparation of this manuscript, Breitenbuecher et al published antibody microarray data showing precisely that in PKC412 resistant AML cells MCL-1 is up-regulated. Subsequently, by using RNA interference, they were able to prove that suppression of MCL-1 rescued PKC412 sensitivity [38]. Since a cytochrome-C-efflux mediated apoptosis is perpetuated through interaction of p53-BAK complexes which then lead to a reduced interaction of MCL-1 and BAK, a differential regulation of two direct counterparts of mitochondrial apoptosis is overt in this setting.…”

Section: Discussionmentioning

confidence: 98%

Mechanisms of resistance against PKC412 in resistant FLT3-ITD positive human acute myeloid leukemia cells

Stölzel

Steudel²,

Oelschlägel³

et al. 2010

Ann Hematol

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Treatment of acute myeloid leukemia (AML) remains challenging with many patients harboring unfavorable prognostic parameters such as FLT3 internal tandem duplication (FLT3-ITD) mutations leading to a constitutively activated FLT3-receptor tyrosine kinase (RTK). Activation of proteins by phosphorylation of tyrosine residues is a common mechanism in leukemia development. Therefore, specific tyrosine kinase inhibitors (TKI) have been developed for AML therapy and are currently under investigation. The staurosporine derivate PKC412 (Midostaurin) was found to be an effective inhibitor of the FLT3-RTK and is currently undergoing clinical trials for FLT3-mutated AML patients. Since resistance towards TKIs has been observed in vitro and in clinical trials, we have generated a PKC412-resistant clone (MV4-11r) of the human myelomonoblastic cell line MV4-11, which carries a homozygous FLT3-ITD mutation. MV4-11r displayed higher vitality after addition of PKC412 compared with MV4-11 with a pronounced reduction of apoptotic cells. Cytogenetic characterization revealed the acquisition of additional aberrations in the resistant cell line such as clonal alterations at chromosome 13q with additional FLT3 signals. Microarray analysis revealed significant expression changes in several genes prior to and after incubation with PKC412. The expression status of candidate genes being regulated by FLT-ITD like JAG1, p53, MCL-1, C-KIT, and FLT3/-L was confirmed by real-time PCR. In summary, resistance against PKC412 appears to be mediated by upregulation of anti-apoptotic genes and down-regulation of proapoptotic signals as well as genes that are involved in normal and malignant hematopoiesis.

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“…For example, increased protein levels of the inhibitor of apoptosis (IAP), survivin, as well as activation of STAT1, STAT3 and STAT5, were observed in ABT-869-resistant MV4-11 cells (Zhou et al, 2009), and antiapoptotic proteins were upregulated in PKC412-resistant MV4-11 cells (Stolzel et al, 2010). Similarly, overexpression of antiapoptotic proteins of the BCL2 family has been found to mediate resistance to FLT3 inhibition in hematopoietic cells with activating FLT3 mutations Mechanisms of resistance to FLT3 inhibition E Weisberg et al (Kohl et al, 2007) and the antiapoptotic protein, MCL-1, was observed to be induced by a non-juxtamembrane ITD that has integrated into the b-2 sheet of the first kinase domain (FLT3_ITD627E) (Brietenbuecher et al, 2009). In association with expression of FLT3-ITD and tyrosine kinase domain mutation dual mutants, which occurs in 1-2% of mutant FLT3-positive patients, there is induction of tyrosine kinase inhibitor and daunorubicin resistance through hyperactivation of STAT5 and consequent upregulation of Bcl-x(L) (Bagrintseva et al, 2005).…”

Section: Aberrant Activation Of Growth and Viability Pathwaysmentioning

confidence: 99%

Drug resistance in mutant FLT3-positive AML

et al. 2010

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Mutant Fms-Like Tyrosine kinase-3 (FLT3), which is expressed in the leukemic cells of a subpopulation of acute myeloid leukemia (AML) patients, represents an attractive target for the therapy of AML. There are several FLT3 inhibitors presently in clinical trials with sufficient efficacy and toxicity features to warrant further testing in combination with standard therapies. However, the transient and partial responses observed in AML patients treated with FLT3 inhibitors, coupled with the discovery of drug-resistant leukemic blast cells in AML patients, have made resistance to FLT3 inhibitors a growing concern. In this study, we provide an overview of the role of mutant FLT3 in AML, FLT3 inhibitors under clinical and preclinical investigation, mechanisms of resistance to FLT3 inhibitors, and possible therapeutic approaches to overcoming this resistance.

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A novel molecular mechanism of primary resistance to FLT3-kinase inhibitors in AML

Cited by 110 publications

References 36 publications

Selective FLT3 inhibitor FI-700 neutralizes Mcl-1 and enhances p53-mediated apoptosis in AML cells with activating mutations of FLT3 through Mcl-1/Noxa axis

Selective FLT3 inhibitor FI-700 neutralizes Mcl-1 and enhances p53-mediated apoptosis in AML cells with activating mutations of FLT3 through Mcl-1/Noxa axis

Mechanisms of resistance against PKC412 in resistant FLT3-ITD positive human acute myeloid leukemia cells

Drug resistance in mutant FLT3-positive AML

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