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
TLDR
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).Abstract:
The PI3K/AKT and mTOR signaling pathways are activated in acute myeloid leukemia, including in the more immature leukemic populations. Constitutive PI3K activation is detectable in 50% of acute myeloid leukemia samples whereas mTORC1 is activated in all cases of this disease. In leukemic cells, the PI3K activity relates to the expression of the p110δ isoform of class IA PI3K. Constitutive PI3K activation is the result of autocrine IGF-1/IGF-1R signaling in 70% of acute myeloid leukemia samples but specific inhibition of this pathway does not induce apoptosis. Specific inhibition of PI3K/AKT or mTORC1 alone in vitro has anti-leukemic effects which are essentially exerted via the suppression of proliferation. However, as mTORC1 activation is independent of PI3K/AKT in acute myeloid leukemia, dual PI3K and mTOR inhibitors may induce apoptosis in blast cells. Moreover, mTORC1 inhibition using sirolimus overactivates PI3K/AKT via the upregulation of IRS2 expression and by favoring IGF-1/IGF-1R autocrine signaling. Recent data also indicate that mTORC1 does not control protein translation in acute myeloid leukemia. These 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).read more
Citations
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Patterns of Somatic Mutation in Human Cancer Genomes
TL;DR: In this paper, the coding exons of the family of 518 protein kinases were sequenced in 210 cancers of diverse histological types to explore the nature of the information that will be derived from cancer genome sequencing.
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Molecular aspects of cancer cell resistance to chemotherapy
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TL;DR: Novel inhibitors of PI3K, Akt, and mTORC1 and 2 are now passing through early phase clinical trials and it is hoped that these agents will circumvent some of the shortcomings of the rapalogs and lead to meaningful benefits for cancer patients.
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AKT/FOXO Signaling Enforces Reversible Differentiation Blockade in Myeloid Leukemias
Stephen M. Sykes,Steven W. Lane,Lars Bullinger,Demetrios Kalaitzidis,Rushdia Z. Yusuf,Borja Saez,Francesca Ferraro,Francois Mercier,Harshabad Singh,Kristina Brumme,Sanket S. Acharya,Claudia Scholl,Zuzana Tothova,Eyal C. Attar,Stefan Fröhling,Ronald A. DePinho,D. Gary Gilliland,Scott A. Armstrong,David T. Scadden +18 more
TL;DR: In this article, the authors show a converse role for AKT/FOXOs in acute myeloid leukemia (AML) and demonstrate that AKT activation is associated with many malignancies, where AKT acts, in part, by inhibiting FOXO tumor suppressors.
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WTAP is a novel oncogenic protein in acute myeloid leukemia
Hima Bansal,Q. Yihua,Swami P. Iyer,Suthakar Ganapathy,David A. Proia,Luiz O. F. Penalva,Philip J. Uren,Uthra Suresh,Jennifer S. Carew,Anand B. Karnad,Steven D. Weitman,Gail E. Tomlinson,Manjeet K. Rao,Steve Kornblau,Sanjay Bansal +14 more
TL;DR: Results provide evidence for an association between the increased expression of WTAP and chemoresistance in AML, and the in vitro transforming activity ofWTAP was examined by investigating its effects on growth of the Ba/F3 cell line.
References
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Journal Article
Patterns of Somatic Mutation in Human Cancer Genomes
TL;DR: In this paper, the coding exons of the family of 518 protein kinases were sequenced in 210 cancers of diverse histological types to explore the nature of the information that will be derived from cancer genome sequencing.
Journal ArticleDOI
Patterns of somatic mutation in human cancer genomes
Christopher Greenman,Philip J. Stephens,Raffaella Smith,Gillian L. Dalgliesh,Christopher I. Hunter,Graham R. Bignell,Helen Davies,Jon W. Teague,Adam Butler,Claire Stevens,Sarah Edkins,Sarah O’Meara,Imre Vastrik,Esther Schmidt,Tim Avis,Syd Barthorpe,Gurpreet Bhamra,Gemma Buck,Bhudipa Choudhury,Jody Clements,Jennifer Cole,Ed Dicks,Simon A. Forbes,Kris Gray,Kelly Halliday,Rachel Harrison,Katy Hills,Jon Hinton,Andy Jenkinson,David T. Jones,Andy Menzies,Tatiana Mironenko,Janet Perry,Keiran Raine,Dave Richardson,Rebecca Shepherd,Alexandra Small,Calli Tofts,Jennifer Varian,Tony Webb,Sofie West,Sara Widaa,Andrew D. Yates,Daniel P. Cahill,David N. Louis,Peter Goldstraw,Andrew G. Nicholson,Francis Brasseur,Leendert H. J. Looijenga,Barbara L. Weber,Yoke Eng Chiew,Anna deFazio,Mel Greaves,Anthony R. Green,Peter J. Campbell,Ewan Birney,Douglas F. Easton,Georgia Chenevix-Trench,Min-Han Tan,Sok Kean Khoo,Bin Tean Teh,Siu Tsan Yuen,Suet Yi Leung,Richard Wooster,P. Andrew Futreal,Michael R. Stratton,Michael R. Stratton +66 more
TL;DR: More than 1,000 somatic mutations found in 274 megabases of DNA corresponding to the coding exons of 518 protein kinase genes in 210 diverse human cancers reveal the evolutionary diversity of cancers and implicates a larger repertoire of cancer genes than previously anticipated.