Cytotoxic activity of the novel Akt inhibitor, MK-2206, in T-cell acute lymphoblastic leukemia

Simioni, Carolina; Neri, Luca M.; Tabellini, Giovanna; Ricci, Francesca; Bressanin, Daniela; Chiarini, Francesca; Evangelisti, Camilla; Cani, Alice; Tazzari, Pierluigi; Melchionda, Fraia; Pagliaro, Pasqualepaolo; Pession, Andrea; McCubrey, James A.; Capitani, Silvano; Martelli, Alberto M.

doi:10.1038/leu.2012.136

Cited by 80 publications

(67 citation statements)

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“…We aimed in investigating the effect of combined Akt and mTOR inhibition on B-pre ALL cells using the novel allosteric, clinically available pan-Akt inhibitor MK-2206. 29 This combination has been demonstrated to be effective in hepatocellular carcinoma cell lines, 53 cholangiocarcinoma cell lines 38 and in an in vivo model of castration-resistant prostate cancer. 54 Moreover, we used a second combination consisting of CCI-779 and GSK 690693.…”

Section: Dual Mtor/akt Inhibition In B-pre All Lm Neri Et Almentioning

confidence: 99%

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Targeting the PI3K/Akt/mTOR signaling pathway in B-precursor acute lymphoblastic leukemia and its therapeutic potential

et al. 2013

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B-precursor acute lymphoblastic leukemia (B-pre ALL) is a malignant disorder characterized by the abnormal proliferation of B-cell progenitors. The prognosis of B-pre ALL has improved in pediatric patients, but the outcome is much less successful in adults. Constitutive activation of the phosphatidylinositol 3-kinase (PI3K), Akt and the mammalian target of rapamycin (mTOR) (PI3K/Akt/ mTOR) network is a feature of B-pre ALL, where it strongly influences cell growth and survival. RAD001, a selective mTORC1 inhibitor, has been shown to be cytotoxic against many types of cancer including hematological malignancies. To investigate whether mTORC1 could represent a target in the therapy of B-pre ALL, we treated cell lines and adult patient primary cells with RAD001. We documented that RAD001 decreased cell viability, induced cell cycle arrest in G 0 /G 1 phase and caused apoptosis in B-pre ALL cell lines. Autophagy was also induced, which was important for the RAD001 cytotoxic effect, as downregulation of Beclin-1 reduced drug cytotoxicity. RAD001 strongly synergized with the novel allosteric Akt inhibitor MK-2206 in both cell lines and patient samples. Similar results were obtained with the combination CCI-779 plus GSK 690693. These findings point out that mTORC1 inhibitors, either as a single agent or in combination with Akt inhibitors, could represent a potential therapeutic innovative strategy in B-pre ALL.

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Section: Dual Mtor/akt Inhibition In B-pre All Lm Neri Et Almentioning

confidence: 99%

“…This method of analysis generally defines CI values from 0.9 to 1.1 as additive, from 0.3 to 0.9 as synergistic and o0.3 as strongly synergistic, whereas values 41.1 are considered as antagonistic. 29 …”

Section: Cell Cycle Analysismentioning

confidence: 99%

Targeting the PI3K/Akt/mTOR signaling pathway in B-precursor acute lymphoblastic leukemia and its therapeutic potential

et al. 2013

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“…3,[14][15][16] As shown in multiple myeloma (MM) cells, autophagy can be induced by inhibiting PI3K/p110d, which normally promotes AKT and mTORC1 activity, or AKT itself. 17,18 In addition, metformin, an anti-diabetic drug that activates AMPK and LKB1, has also been shown to activate autophagy in T-ALL cells. 19 Lithium, carbemazepine and valproate, that are used to treat a range of neurological and psychiatric conditions (and, in the case of sodium valproate, also hematologic malignancies), 20 induce autophagy by activating inositol monophosphatase (IMPase).…”

Section: Autophagy-activating Stimuli and Autophagy Inhibitorsmentioning

confidence: 99%

Autophagy in blood cancers: biological role and therapeutic implications

Nencioni¹,

Cea²,

Montecucco³

et al. 2013

Haematologica

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Autophagy is a cell recycling process the molecular apparatus of which has been identified over the past decade. Autophagy allows cells to survive starvation and inhospitable conditions and plays a key role in numerous physiological functions, including hematopoiesis and immune responses. In hematologic malignancies, autophagy can either act as a chemo-resistance mechanism or have tumor suppressive functions, depending on the context. In addition, autophagy is involved in other important aspects of blood cancers as it promotes immune competence and anticancer immunity, and may even help enhance patient tolerance to standard treatments. Approaches exploiting autophagy, either to activate or inhibit it, could find broad application in hematologic malignancies and contribute to improved clinical outcomes. These aspects are discussed here together with a brief introduction to the molecular machinery of autophagy and to its role in blood cell physiology. ABSTRACT

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“…In addition, MK-2206 decreases T-acute lymphocytic leukemia cell viability by arresting the cells in the G0/G1 phase of the cell cycle, and by inducing apoptosis with IC50 values ranging between 1.7 and 5.1 μM. 72 It has also been shown that inhibition of PI3K/AKT signaling by MK-2206 affects the growth of both JAK2 V617F-or MPLW515L-expressing primary neoplastic cells and cell lines via reduced phosphorylation of AKT and inhibition of its downstream signaling molecules. 73 In the same study, MK-2206 alleviated hepato-splenomegaly and reduced the megakaryocyte burden in the BM, liver and spleen of mice with MPL W515L-induced MPN.…”

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Co-operating STAT5 and AKT signaling pathways in chronic myeloid leukemia and mastocytosis: possible new targets of therapy

et al. 2014

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417 IntroductionSeveral new targets have recently been identified in neoplastic mast cells (MCs), and various targeted drugs have been examined for their effectiveness in malignant MC disorders. However, most drugs, including new KIT D816V-blocking agents, such as midostaurin (PKC412), 1 and various BCR-ABL1 inhibitors known to block KIT-activity, such as imatinib or dasatinib, 2 have failed to achieve long-lasting remissions in aggressive systemic mastocytosis (ASM). There is a similar problem in Ph + CML, where imatinib-resistant patients do not reach molecular remission even when secondor third-line BCR-ABL1 tyrosine kinase inhibitors (TKIs) are applied, particularly in patients exhibiting the BCR-ABL1 T315I mutant.3 During disease progression, additional signal transduction pathways become activated in neoplastic cells. Among these, AKT and STAT5 are critical downstream signaling molecules constitutively phosphorylated imatinibresistant chronic myeloid leukemia (CML) and KIT D816V + SM. 4,5 This has been demonstrated in vitro using KIT D816V + and BCR-ABL1 + imatinib-resistant cell lines, where inhibition of phosphorylation of these targets has shown their crucial role in cell proliferation. 6,7 It has also been reported that STAT5 and AKT remained activated in neoplastic myeloid cells, even after inhibition of BCR-ABL1 by TKIs. 8 Moreover, during disease progression, the levels of STAT5 mRNA and protein increase, and STAT5 production and activation is triggered not only by BCR-ABL1 or mutant KIT, but also by other pro-oncogenic pathways relevant to disease progression and resistance. 9 Taken together, these observations strongly suggest that STAT5 and AKT are key drivers in drug-resistant CML and SM, and thus represent potential therapeutic targets. Small molecules targeting STAT5 or AKT may indeed be effective in these malignancies, especially in TKIs-resistant patients. However, inhibitors available today, such as pimozide or BP-1-108 for STAT5, 10,11 or perifosine for AKT,12 are neither specific nor potent enough to be applicable in clinical practice. Therefore, it seems important to develop compounds that specifically and potently target STAT5 and AKT. Mast cells and mastocytosis KIT and cytokine signaling in normal mast cellsMCs originate from bone marrow (BM)-derived hematopoietic stem cells (HSCs) that enter the peripheral tissues via the bloodstream and undergo maturation under the Co-operating STAT5 and AKT signaling pathways in chronic myeloid leukemia and mastocytosis: possible new targets of therapy open-access paper. doi:10.3324/haematol.2013.098442 Manuscript received on October 8, 2013. Manuscript accepted on December 20, 2013 Chronic myeloid leukemia and systemic mastocytosis are myeloid neoplasms sharing a number of pathogenetic and clinical features. In both conditions, an aberrantly activated oncoprotein with tyrosine kinase activity, namely BCR-ABL1 in chronic myeloid leukemia, and mutant KIT, mostly KIT D816V, in systemic mastocytosis, is key to disease evolution. The appreciation of...

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Cytotoxic activity of the novel Akt inhibitor, MK-2206, in T-cell acute lymphoblastic leukemia

Cited by 80 publications

References 40 publications

Targeting the PI3K/Akt/mTOR signaling pathway in B-precursor acute lymphoblastic leukemia and its therapeutic potential

Targeting the PI3K/Akt/mTOR signaling pathway in B-precursor acute lymphoblastic leukemia and its therapeutic potential

Autophagy in blood cancers: biological role and therapeutic implications

Co-operating STAT5 and AKT signaling pathways in chronic myeloid leukemia and mastocytosis: possible new targets of therapy

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