Targeting of mTORC1/2 by the mTOR kinase inhibitor PP242 induces apoptosis in AML cells under conditions mimicking the bone marrow microenvironment

Zeng, Zhihong; Shi, Yue; Tsao, Twee; Qiu, Yihua; Kornblau, Steven M.; Baggerly, Keith A.; Liu, Wenbin; Jessen, Katti; Liu, Yi; Kantarjian, Hagop; Rommel, Christian; Fruman, David A.; Andreeff, Michael; Konopleva, Marina

doi:10.1182/blood-2011-11-393934

Cited by 107 publications

(74 citation statements)

References 39 publications

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“…Because constitutive activation of AKT is the most common pathway abnormality in AML, dual PI3K/mTOR inhibitors (PI-103, BEZ235), mTORC1/2 inhibitors (OSI-027, PP242), and AKT inhibitors (perifosine) have been investigated in preclinical models and, at least in vitro, appear to be more effective than rapalogs. [183][184][185][186][187] Based on these results, early-phase clinical trials are ongoing in adults.…”

Section: Acute and Chronic Myelogenous Leukemiamentioning

confidence: 99%

Targeting the PI3K/AKT/mTOR Signaling Axis in Children with Hematologic Malignancies

et al. 2012

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The phosphatidylinositiol 3-kinase (PI3K), AKT, mammalian target of rapamycin (mTOR) signaling pathway (PI3K/AKT/mTOR) is frequently dysregulated in disorders of cell growth and survival, including a number of pediatric hematologic malignancies. The pathway can be abnormally activated in childhood acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), and chronic myelogenous leukemia (CML), as well as in some pediatric lymphomas and lymphoproliferative disorders. Most commonly, this abnormal activation occurs as a consequence of constitutive activation of AKT, providing a compelling rationale to target this pathway in many of these conditions. A variety of agents, beginning with the rapamycin analogue (rapalog) sirolimus, have been used successfully to target this pathway in a number of pediatric hematologic malignancies. Rapalogs demonstrate significant preclinical activity against ALL, which has led to a number of clinical trials. Moreover, rapalogs can synergize with a number of conventional cytotoxic agents and overcome pathways of chemotherapeutic resistance for drugs commonly used in ALL treatment, including methotrexate and corticosteroids. Based on preclinical data, rapalogs are also being studied in AML, CML, and non-Hodgkin's lymphoma. Recently, significant progress has been made using rapalogs to treat pre-malignant lymphoproliferative disorders, including the autoimmune lymphoproliferative syndrome (ALPS); complete remissions in children with otherwise therapy-resistant disease have been seen.Rapalogs only block one component of the pathway (mTORC1), and newer agents are under preclinical and clinical development that can target different and often multiple protein kinases in the PI3K/AKT/mTOR pathway. Most of these agents have been tolerated in early-phase clinical trials. A number of PI3K inhibitors are under investigation. Of note, most of these also target other protein kinases. Newer agents are under development that target both mTORC1 and mTORC2, mTORC1 and PI3K, and the triad of PI3K, mTORC1, and mTORC2. Preclinical data suggest these dual-and multi-kinase inhibitors are more potent than rapalogs against many of the aforementioned hematologic malignancies. Two classes of AKT inhibitors are under development, the alkyl-lysophospholipids (APLs) and small molecule AKT inhibitors. Both classes have agents currently in clinical trials. A number of drugs are in development that target other components of the pathway, including eukaryotic translation initiation factor (eIF) 4E (eIF4E) and phosphoinositide-dependent protein kinase 1 (PDK1). Finally, a number of other key signaling pathways interact with PI3K/AKT/mTOR, including Notch, MNK, Syk, MAPK, and aurora kinase. These alternative pathways are being targeted alone and in combination with PI3K/AKT/mTOR inhibitors with promising preclinical results in pediatric hematologic malignancies. This review provides a comprehensive overview of the abnormalities in the PI3K/AKT/mTOR signaling pathway in pediatric hematologic malignanc...

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Section: Acute and Chronic Myelogenous Leukemiamentioning

confidence: 99%

Targeting the PI3K/AKT/mTOR Signaling Axis in Children with Hematologic Malignancies

et al. 2012

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“…Importantly, treatment with PP242, another known mTOR kinase inhibitor [36], had no significant effect on the assembling of mTORC1 and mTORC2 in TPC-1 cells (Fig. 4G).…”

Section: Resultsmentioning

confidence: 99%

The mTOR Kinase Inhibitor CZ415 Inhibits Human Papillary Thyroid Carcinoma Cell Growth

Song

et al. 2018

Cell Physiol Biochem

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Background/Aim: Mammalian target of rapamycin (mTOR) plays an important role in papillary thyroid carcinoma (PTC) cell progression. CZ415 is a novel, highly-efficient and specific mTOR kinase inhibitor. The current study tested the potential anti-tumor activity of CZ415 in human PTC cells. Methods: The established (TPC-1 cell line) and primary human PTC cells were treated with CZ415. Cell survival and growth were tested by Cell Counting Kit-8 assay and BrdU ELISA assay, respectively. Cell apoptosis was tested by caspase-3/-9 activity assay, Hoechst-33342 staining assay and single-stranded DNA ELISA assay. Cell cycle progression was tested by propidium iodide-FACS assay. The mTOR signaling was tested by Western blotting assay and co-immunoprecipitation assay. The mouse xenograft tumor model was applied to study the effect of CZ415 in vivo. Results: In cultured human PTC cells, treatment with CZ415 at nM concentrations significantly inhibited cell survival and growth. CZ415 induced apoptosis activation and cell cycle arrest in human PTC cells. CZ415 disrupted assembling of mTORC1 (mTOR-Raptor association) and mTORC2 (mTOR-Rictor-GβL association) in TPC-1 cells, which led to de-phosphorylation of the mTORC1 substrates (S6K1 and 4E-BP1) and the mTORC2 substrate AKT (Ser-473). Further studies show that the autophagy inhibitor 3-methyladenine (3-MA) or Beclin-1 shRNA aggravated CZ415-induced cytotoxicity against PTC cells. In vivo, CZ415 oral administration inhibited TPC-1 xenograft tumor growth in mice. Conclusion: Our results show that mTOR blockage by CZ415 inhibits PTC cell growth in vitro and in vivo.

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“…AZD8055 induced the caspase-dependent apoptosis and autophagy of AML cell lines in vitro [91]. PP242 was shown to suppress B-ALL, T-ALL, and AML cells by inhibiting the PI3K/AKT/mTOR pathway and prolonging survival in AML mouse models [92][93][94]. Torin-2, an ATP-competitive inhibitor of mTOR, causes both apoptosis and autophagy and suppresses the cell cycle by affecting both mTORC1 and mTORC2 activities [93,95].…”

Section: Targeting Mtor Signaling For Leukemia Therapymentioning

confidence: 99%

mTORC signaling in hematopoiesis

et al. 2016

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Targeting of mTORC1/2 by the mTOR kinase inhibitor PP242 induces apoptosis in AML cells under conditions mimicking the bone marrow microenvironment

Cited by 107 publications

References 39 publications

Targeting the PI3K/AKT/mTOR Signaling Axis in Children with Hematologic Malignancies

Targeting the PI3K/AKT/mTOR Signaling Axis in Children with Hematologic Malignancies

The mTOR Kinase Inhibitor CZ415 Inhibits Human Papillary Thyroid Carcinoma Cell Growth

mTORC signaling in hematopoiesis

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