Antileukemic activity of rapamycin in acute myeloid leukemia

Abstract

The mammalian target of rapamycin (mTOR) is a key regulator of growth and survival in many cell types. Its constitutive activation has been involved in the pathogenesis of various cancers. In this study, we show that mTOR inhibition by rapamycin strongly inhibits the growth of the most immature acute myeloid leukemia ( IntroductionAcute myeloid leukemia (AML) is a clonal disorder characterized by accumulation of malignant hematopoietic progenitor cells (HPCs) with impaired differentiation program. Despite important progress in the therapy of AML and high rates of complete remission after induction chemotherapy, most patients will relapse and die from the disease. Prevention of relapse is based on intensified programs, including high-dose chemotherapy and autologous or allogenic transplants that can benefit young patients. Thus, outcome of patients older than 60 years has not been improved for decades, underlying the need for potent and less toxic drugs for the treatment of this disease. 1 Recent studies have demonstrated that AML cells are characterized by recurrent mutations of genes involved in cell differentiation, survival, and proliferation. A pathogenesis model for AML suggests that mutations of both tyrosine kinase receptors and transcription factors, by conferring survival and/or proliferative advantage (class I mutation) and by impairing cell differentiation (class II mutation), are needed to cause leukemia. 2 Fms-like tyrosine kinase 3 (FLT3), c-KIT, and RAS mutations occur in 50% to 60% of AML cases, 3-7 leading to aberrant activation of major cell survival or proliferation pathways such as mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase (PI3K)/ Akt, signal transducer and activator of transcription (STAT), or nuclear factor B (NF-kB). [8][9][10] These antiapoptotic signaling pathways also contribute to AML resistance to the cytotoxic agents currently used in this disease. 11,12 Thus, therapeutic interference with these pathways represents an attractive strategy in AML therapy. In this context, current clinical trials are evaluating new compounds directly targeting RAS or FLT3 (eg, farnesyl transferase inhibitors; CEP-701 and PKC 412). 13,14 Molecules integrating multiple signal transduction pathways may represent relevant therapeutic targets in AML. Mammalian target of rapamycin (mTOR) is a serine/threonine kinase involved in the regulation of cell growth and proliferation by translational control of key proteins such as the cyclin-dependent kinase (CDK) inhibitor p27kip1, retinoblastoma protein, cyclin D1, c-myc, or STAT 3. mTOR is activated by different stimuli including nutrients or growth factors. 15,16 Once activated, mTOR can phosphorylate its downstream targets, the ribosomal p70S6 kinase (p70S6K) and the 4E-binding protein 1 (4E-BP1). There are 2 known isoforms of S6K, p70 and p85, generated from differential splicing from a common gene. The p85S6K isoform is identical to p70S6K, except for a 23-amino acid extension at the amino-terminus that specifically targets it to ...

Longitudinal inhibition of PI3K/Akt/mTOR signaling by LY294002 and rapamycin induces growth arrest of adult T-cell leukemia cells

“…Blockade of mTOR by rapamycin and its derivative RAD001 inhibited proliferation of HTLV-1 infected cells (Figs 2,3). Also, RAD001 was shown to inhibit proliferation of acute myeloid leukemia cells and sensitize these cells to growth inhibition mediated by cytotoxic agents such as cytarabine [23,24]. A [25].…”

Somatic stem cells and the origin of cancer

“…In PTEN deficient mouse, the PI3K pathway is constitutively activated, which in turn activates the mammalian target of rapamycin (mTOR). The drug rapamycin inhibits mTOR kinase activity [87][88][89] .…”

Calcineurin inhibitor-free GVHD prophylaxis with sirolimus, mycophenolate mofetil and ATG in Allo-SCT for leukemia patients with high relapse risk: an observational cohort study

“…20 Inhibition of mTOR with rapamycin inhibits proliferation of cells from patients with AML and FLT3 mutations, and in patients with relapsed/refractory or poor-risk AML, sirolimus has been reported to induce significant clinical responses as a single agent. 21 Similarly, the mTOR pathway seems to play a critical role in the pathogenesis of T-ALL, where it is deregulated as a downstream target by constitutive NOTCH activation, and T-ALL cell growth was suppressed in a highly synergistic manner by simultaneous treatment with the mTOR inhibitor sirolimus and NOTCH blockade by g-secretase inhibitors. 22 The most important adverse reactions attributable to sirolimus are reversible cytopenias, 23 interstitial pneumonitis, 24 cutaneous reactions and mucosal ulcers, 25,26 hyperlipidemia 27 and impaired wound healing.…”