PI-103, a dual inhibitor of Class IA phosphatidylinositide 3-kinase and mTOR, has antileukemic activity in AML
Sophie Park,Nicolas Chapuis,Nicolas Chapuis,Valérie Bardet,Jerome Tamburini,Jerome Tamburini,Nathalie Gallay,Lise Willems,Lise Willems,Zachary A. Knight,Kevan M. Shokat,Nabih Azar,Franck Viguié,Norbert Ifrah,Francois Dreyfus,Patrick Mayeux,Patrick Mayeux,Catherine Lacombe,Didier Bouscary +18 more
TLDR
It is demonstrated that multitargeted therapy against PI3K/Akt and mTOR with PI-103 may be of therapeutic value in AML.Abstract:
The phosphatidylinositol 3-kinase (PI3K)/Akt and mammalian target of rapamycin complex 1 (mTORC1) signaling pathways are frequently activated in acute myelogenous leukemia (AML). mTORC1 inhibition with RAD001 induces PI3K/Akt activation and both pathways are activated independently, providing a rationale for dual inhibition of both pathways. PI-103 is a new potent PI3K/Akt and mTOR inhibitor. In human leukemic cell lines and in primary blast cells from AML patients, PI-103 inhibited constitutive and growth factor-induced PI3K/Akt and mTORC1 activation. PI-103 was essentially cytostatic for cell lines and induced cell cycle arrest in the G1 phase. In blast cells, PI-103 inhibited leukemic proliferation, the clonogenicity of leukemic progenitors and induced mitochondrial apoptosis, especially in the compartment containing leukemic stem cells. In contrast, apoptosis was not induced with RAD001 and IC87114 association, which specifically inhibits mTORC1 and p110delta activity, respectively. PI-103 had additive proapoptotic effects with etoposide in blast cells and in immature leukemic cells. Interestingly, PI-103 did not induce apoptosis in normal CD34(+) cells and had moderate effects on their clonogenic and proliferative properties. Here, we demonstrate that multitargeted therapy against PI3K/Akt and mTOR with PI-103 may be of therapeutic value in AML.read more
Citations
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Next-generation mTOR inhibitors in clinical oncology: how pathway complexity informs therapeutic strategy.
TL;DR: A brief overview of the signaling pathways up- and downstream of mTORC1 and -2 is provided, and the insights into therapeutic anticancer targets - both those that have been tried in the clinic with limited success and those currently under clinical development - that knowledge of these pathways gives us.
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Effective and selective targeting of leukemia cells using a TORC1/2 kinase inhibitor
Matthew R. Janes,Jose J. Limon,Lomon So,Jing Chen,Raymond J Lim,Melissa A Chavez,Collin Vu,Michael B. Lilly,Sharmila Mallya,S. Tiong Ong,Marina Konopleva,Michael B. Martin,Pingda Ren,Yi Liu,Christian Rommel,David A. Fruman +15 more
TL;DR: It is established that Ph+ transformed cells are more sensitive than normal lymphocytes to selective TORC1/2 inhibitors and support the development of such inhibitors for leukemia therapy.
Journal ArticleDOI
Constitutively active AKT depletes hematopoietic stem cells and induces leukemia in mice
Michael G. Kharas,Rachel Okabe,Jared J. Ganis,Jared J. Ganis,Maricel Gozo,Tulasi Khandan,Mahnaz Paktinat,D. Gary Gilliland,Kira Gritsman,Kira Gritsman +9 more
TL;DR: It is demonstrated that enhanced AKT activation is an important mechanism of transformation in AML and that HSCs are highly sensitive to excess AKT/mTOR signaling.
Journal ArticleDOI
Role of the PI3K/AKT and mTOR signaling pathways in acute myeloid leukemia
Sophie Park,Nicolas Chapuis,Jerome Tamburini,Valérie Bardet,Pascale Cornillet-Lefebvre,Lise Willems,Alexa S. Green,Patrick Mayeux,Catherine Lacombe,Didier Bouscary +9 more
TL;DR: The results open the way for the design of direct inhibitors of protein synthesis as novel acute myeloid leukemia therapies and also for the development of second generation mTOR inhibitors (the TORKinhibs).
Journal ArticleDOI
The phosphatidylinositol 3-kinase/Akt/mTOR signaling network as a therapeutic target in acute myelogenous leukemia patients.
TL;DR: This review highlights how the PI3K/Akt/mTOR signaling axis is constitutively active in AML patients, where it affects survival, proliferation, and drug-resistance of leukemic cells includingLeukemic stem cells.
References
More filters
Journal ArticleDOI
TOR signaling in growth and metabolism.
TL;DR: The physiological consequences of mammalianTORC1 dysregulation suggest that inhibitors of mammalian TOR may be useful in the treatment of cancer, cardiovascular disease, autoimmunity, and metabolic disorders.
Journal ArticleDOI
A quantitative analysis of kinase inhibitor selectivity.
Mazen W. Karaman,Sanna Herrgard,Daniel K. Treiber,Paul Gallant,Corey E. Atteridge,Brian T. Campbell,Katrina W Chan,Pietro Ciceri,Mindy I. Davis,Philip T. Edeen,Raffaella Faraoni,Mark Floyd,Jeremy P. Hunt,Daniel J Lockhart,Zdravko V. Milanov,Michael J Morrison,Gabriel Pallares,Hitesh K. Patel,Stephanie Pritchard,Stephanie Pritchard,Lisa M. Wodicka,Patrick P. Zarrinkar +21 more
TL;DR: This work presents interaction maps for 38 kinase inhibitors across a panel of 317 kinases representing >50% of the predicted human protein kinome and introduces the concept of a selectivity score as a general tool to quantify and differentiate the observed interaction patterns.
Journal ArticleDOI
A Pharmacological Map of the PI3-K Family Defines a Role for p110α in Insulin Signaling
Zachary A. Knight,Beatriz González,Morri E. Feldman,Eli R. Zunder,David D. Goldenberg,Olusegun Williams,Robbie Loewith,David Stokoe,András Balla,Balazs Toth,Tamas Balla,William A. Weiss,Roger L. Williams,Kevan M. Shokat +13 more
TL;DR: It is found that p110alpha is the primary insulin-responsive PI3-K in cultured cells, whereas p110beta is dispensable but sets a phenotypic threshold for p110 alpha activity, which illustrates systematic target validation using a matrix of inhibitors that span a protein family.
Journal ArticleDOI
Normal and leukemic hematopoiesis: Are leukemias a stem cell disorder or a reacquisition of stem cell characteristics?
TL;DR: Identifying the LSCs for each type of leukemia is a current challenge and a critical step in understanding their respective biologies and may provide key insights into more effective treatments.
Journal ArticleDOI
A dual PI3 kinase/mTOR inhibitor reveals emergent efficacy in glioma
Qi-Wen Fan,Zachary A. Knight,David D. Goldenberg,Wei Yu,Keith E. Mostov,David Stokoe,Kevan M. Shokat,William A. Weiss +7 more
TL;DR: Surprisingly, a single agent (PI-103) effected proliferative arrest in glioma cells, despite the ability of many compounds to block PI3 kinase signaling through its downstream effector, Akt.