Lack of antileukemic activity of rapamycin in elderly patients with acute myeloid leukemia evolving from a myelodysplastic syndrome

Callera, Fernando; Lopes, Carlos O.; Rosa, Evandro Secchi; Mulin, Carla Cecília

doi:10.1016/j.leukres.2008.02.004

Cited by 17 publications

(14 citation statements)

References 8 publications

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“…In addition, CCI-779 (temsirolimus) has been shown to co-operate with ABT-737 (Bcl-2 family proteins inhibitor) to induce apoptotic cell death in acute lymphoblastic leukemia (ALL), which was accompanied by downregulation of Mcl-1 expression [71]. Unfortunately, the efficacy of rapamycin analogs in leukemia treatment has been clinically lower than expected [72, 73, 11]. Directly blocking mTORC1 activity results in only some cytostatic effects on AML cells in vitro [67].…”

Section: Strategies For Targeting Eif4e In Amlmentioning

confidence: 99%

Dual targeting of eIF4E by blocking MNK and mTOR pathways in leukemia

2017

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Dysregulation of mRNA translation leads to aberrant activation of cellular pathways that promote expansion and survival of leukemic clones. A key element of the initiation translation complex is eIF4E (eukaryotic translation initiation factor 4E). The mitogen-activated protein kinase (MAPK) and mammalian target of rapamycin (mTOR) pathways play important roles in the regulation of eIF4E expression and downstream functional outcomes. Mitogen-activated protein kinase interacting protein kinases (Mnks) control translation by phosphorylation of eIF4E, whereas the mTOR kinase phosphorylates/de-activates the eIF4E inhibitor, 4E-BP1, to release translational repression. Both pathways are often abnormally activated in leukemia cells and promote cell survival events by controlling expression of oncogenic proteins. Targeting these pathways may provide approaches to avoid aberrant proliferation and neoplastic transformation.

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Section: Strategies For Targeting Eif4e In Amlmentioning

confidence: 99%

Dual targeting of eIF4E by blocking MNK and mTOR pathways in leukemia

2017

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“…PI3K/AKT/mTOR may be an important therapeutic target in AML. Unfortunately, targeting the mTOR pathway with single-agent rapamycin in clinical trials was unsuccessful (37). As an alternative to adding chemotherapy, it is useful to target both the mTOR pathway and other cancer targets to generate more effective responses (38,39).…”

Section: Discussionmentioning

confidence: 99%

Inhibiting PLK1 induces autophagy of acute myeloid leukemia cells via mammalian target of rapamycin pathway dephosphorylation

Tao

et al. 2017

Oncology Reports

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Decreased autophagy is accompanied by the development of a myeloproliferative state or acute myeloid leukemia (AML). AML cells are often sensitive to autophagy-inducing stimuli, prompting the idea that targeting autophagy can be useful in AML cytotoxic therapy. AML NB4 cells overexpressing microtubule-associated protein 1 light chain 3-green fluorescent protein were screened with 69 inhibitors to analyze autophagy activity. AML cells were treated with the polo-like kinase 1 (PLK1) inhibitors RO3280 and BI2536 before autophagy analysis. Cleaved LC3 (LC3-II) and the phosphorylation of mammalian target of rapamycin (mTOR), adenosine monophosphate-activated protein kinase, and Unc-51-like kinase 1 during autophagy was detected with western blotting. Autophagosomes were detected using transmission electron microscopy. Several inhibitors had promising autophagy inducer effects: BI2536, MLN0905, SK1-I, SBE13 HCL and RO3280. Moreover, these inhibitors all targeted PLK1. Autophagy activity was increased in the NB4 cells treated with RO3280 and BI2536. Inhibition of PLK1 expression in NB4, K562 and HL-60 leukemia cells with RNA interference increased LC3-II and autophagy activity. The phosphorylation of mTOR was reduced significantly in NB4 cells treated with RO3280 and BI2536, and was also reduced significantly when PLK1 expression was downregulated in the NB4, K562 and HL-60 cells. We demonstrate that PLK1 inhibition induces AML cell autophagy and that it results in mTOR dephosphorylation. These results may provide new insights into the molecular mechanism of PLK1 in regulating autophagy.

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“…13,[81][82][83][84] In general, the rapalogs' clinical activity in AML is modest at best (Table 1). 83,[85][86][87] In a phase I trial that assessed the rapalog deferolimus among 23 AML patients, none achieved a response. 88 A phase I/II study of everolimus in nine AML patients also resulted in no bone marrow responses.…”

Section: Mtorc1/mtorc2mentioning

confidence: 99%

Targeting mTOR signaling pathways and related negative feedback loops for the treatment of acute myeloid leukemia

Carneiro

Kaplan

Altman

et al. 2015

Cancer Biology & Therapy

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An accumulating understanding of the complex pathogenesis of acute myeloid leukemia (AML) continues to lead to promising therapeutic approaches. Among the key aberrant intracellular signaling pathways involved in AML, the phosphatidylinositol 3-kinase/AKT/mammalian target of rapamycin (PI3K/AKT/mTOR) axis is of major interest. This axis modulates a wide array of critical cellular functions, including proliferation, metabolism, and survival. Pharmacologic inhibitors of components of this pathway have been developed over the past decade, but none has an established role in the treatment of AML. This review will discuss the preclinical data and clinical results driving ongoing attempts to exploit the PI3K/AKT/mTOR pathway in patients with AML and address issues related to negative feedback loops that account for leukemic cell survival. Targeting the PI3K/AKT/mTOR pathway is of high interest for the treatment of AML, but combination therapies with other targeted agents may be needed to block negative feedback loops in leukemia cells.

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Lack of antileukemic activity of rapamycin in elderly patients with acute myeloid leukemia evolving from a myelodysplastic syndrome

Cited by 17 publications

References 8 publications

Dual targeting of eIF4E by blocking MNK and mTOR pathways in leukemia

Dual targeting of eIF4E by blocking MNK and mTOR pathways in leukemia

Inhibiting PLK1 induces autophagy of acute myeloid leukemia cells via mammalian target of rapamycin pathway dephosphorylation

Targeting mTOR signaling pathways and related negative feedback loops for the treatment of acute myeloid leukemia

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