Heat shock protein 90 inhibition is cytotoxic to primary AML cells expressing mutant FLT3 and results in altered downstream signalling

Shaer, Laila Al; Walsby, Elisabeth Jane; Gilkes, Amanda F.; Tonks, Amanda Jayne; Walsh, V.; Mills, Ken I.; Burnett, Alan Kenneth; Rowntree, Clare

doi:10.1111/j.1365-2141.2008.07053.x

Cited by 45 publications

(36 citation statements)

References 38 publications

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“…54,55 Conversely, in the arginase-resistant cells, overexpression of the heat shock protein HSPA6 was demonstrated, suggesting that this may be a mechanism by which these cells attain resistance, especially in light of the finding that HSP inhibition is cytotoxic to AML. 56 EREG and EGFR signaling, as well as the heat shock protein family, play key roles in solid tumor cell proliferation. Small-molecule inhibitors are currently under development in AML to target these pathways, providing the potential for rational combinations of other drugs with BCT-100 for maximal anti-leukemia effect.…”

Section: Discussionmentioning

confidence: 99%

Arginine dependence of acute myeloid leukemia blast proliferation: a novel therapeutic target

Mussai

Egan

Higginbotham-Jones

et al. 2015

Blood

139

153

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Key Points• Arginase depletion with BCT-100 pegylated recombinant human arginase is cytotoxic to AML blasts.Acute myeloid leukemia (AML) is one of the most common acute leukemias in adults and children, yet significant numbers of patients relapse and die of disease. In this study, we identify the dependence of AML blasts on arginine for proliferation. We show that AML blasts constitutively express the arginine transporters CAT-1 and CAT-2B, and that the majority of newly diagnosed patients' blasts have deficiencies in the arginine-recycling pathway enzymes argininosuccinate synthase and ornithine transcarbamylase, making them arginine auxotrophic. BCT-100, a pegylated human recombinant arginase, leads to a rapid depletion in extracellular and intracellular arginine concentrations, resulting in arrest of AML blast proliferation and a reduction in AML engraftment in vivo. BCT-100 as a single agent causes significant death of AML blasts from adults and children, and acts synergistically in combination with cytarabine. Using RNA sequencing, 20 further candidate genes which correlated with resistance have been identified. Thus, AML blasts are dependent on arginine for survival and proliferation, as well as depletion of arginine with BCT-100 of clinical value in the treatment of AML. (Blood. 2015;125(15):2386-2396

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Section: Discussionmentioning

confidence: 99%

Arginine dependence of acute myeloid leukemia blast proliferation: a novel therapeutic target

Mussai

Egan

Higginbotham-Jones

et al. 2015

Blood

139

153

View full text Add to dashboard Cite

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“…[1][2][3] Extensive preclinical studies have examined this chaperone as a potential new drug target in hematologic malignancies. [3][4][5][6][7] Among the more than 80 currently identified Hsp90 client proteins there are several kinases involved in myeloid neoplasms, including Bcr/abl, 8,9 Flt3, 4,10,11 and c-Kit, 12 as well as the anti-apoptotic kinase Akt. 13,14 When Hsp90 is inhibited, these polypeptides and other Hsp90 clients fail to fold properly during synthesis and, as a consequence, become less abundant as mature molecules turn over.…”

Section: Introductionmentioning

confidence: 99%

Phase I and pharmacological study of cytarabine and tanespimycin in relapsed and refractory acute leukemia

Kaufmann¹,

Karp²,

Litzow³

et al. 2011

Haematologica

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BackgroundIn preclinical studies the heat shock protein 90 (Hsp90) inhibitor tanespimycin induced downregulation of checkpoint kinase 1 (Chk1) and other client proteins as well as increased sensitivity of acute leukemia cells to cytarabine. We report here the results of a phase I and pharmacological study of the cytarabine + tanespimycin combination in adults with recurrent or refractory acute leukemia. Design and MethodsPatients received cytarabine 400 mg/m 2 /day continuously for 5 days and tanespimycin infusions at escalating doses on days 3 and 6. Marrow mononuclear cells harvested before therapy, immediately prior to tanespimycin, and 24 hours later were examined by immunoblotting for Hsp70 and multiple Hsp90 clients. ResultsTwenty-six patients were treated at five dose levels. The maximum tolerated dose was cytarabine 400 mg/m 2 /day for 5 days along with tanespimycin 300 mg/m 2 on days 3 and 6. Treatment-related adverse events included disseminated intravascular coagulation (grades 3 and 5), acute respiratory distress syndrome (grade 4), and myocardial infarction associated with prolonged exposure to tanespimycin and its active metabolite 17-aminogeldanamycin. Among 21 evaluable patients, there were two complete and four partial remissions. Elevations of Hsp70, a marker used to assess Hsp90 inhibition in other studies, were observed in more than 80% of samples harvested 24 hours after tanespimycin, but down-regulation of Chk1 and other Hsp90 client proteins was modest. ConclusionsBecause exposure to potentially effective concentrations occurs only for a brief time in vivo, at clinically tolerable doses tanespimycin has little effect on resistance-mediating client proteins in relapsed leukemia and exhibits limited activity in combination with cytarabine. (Clinicaltrials.gov identifier: NCT00098423).

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“…Mutant FLT3-positive AML cells are killed by rapamycin, because of its inhibition of mTOR, another downstream effector of the PI3K/Akt signaling pathway (Recher et al, 2005). Similarly, AML cells expressing mutant FLT3 are killed by inhibition of the mutant FLT3 chaperone, heat-shock protein 90 (Hsp90), which interferes with JAK/STAT, RAS/Raf/MEK/ERK and PI3K/Akt signaling (Al Shaer et al, 2008). A schematic of FLT3 signaling is shown in Figure 2.…”

Section: Mutant Flt3 and Cell Signalingmentioning

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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Heat shock protein 90 inhibition is cytotoxic to primary AML cells expressing mutant FLT3 and results in altered downstream signalling

Cited by 45 publications

References 38 publications

Arginine dependence of acute myeloid leukemia blast proliferation: a novel therapeutic target

Arginine dependence of acute myeloid leukemia blast proliferation: a novel therapeutic target

Phase I and pharmacological study of cytarabine and tanespimycin in relapsed and refractory acute leukemia

Drug resistance in mutant FLT3-positive AML

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