Selective targeting of the mTORC1/2 protein kinase complexes leads to antileukemic effects in vitro and in vivo
Open Access
- 2 September 2011
- journal article
- research article
- Published by Springer Science and Business Media LLC in Blood Cancer Journal
- Vol. 1 (9), e34
- https://doi.org/10.1038/bcj.2011.30
Abstract
The BCR/ABL tyrosine kinase promotes leukemogenesis through activation of several targets that include the phosphoinositide 3-kinase (PI3K). Tyrosine kinase inhibitors (TKIs), which target BCR/ABL, induce striking clinical responses. However, therapy with TKIs is associated with limitations such as drug intolerance, inability to universally eradicate the disease and emergence of BCR/ABL drug-resistant mutants. To overcome these limitations, we tested whether inhibition of the PI3K/target of rapamycin (mTOR) signaling pathway has antileukemic effect in primary hematopoietic stem cells and BA/F3 cells expressing the BCR/ABL oncoprotein. We determined that dual inhibition of PI3K/mTOR causes growth arrest and apoptosis leading to profound antileukemic effects both in vitro and in vivo. We also established that pharmacologic inhibition of the mTORC1/mTORC2 complexes is sufficient to cause these antileukemic effects. Our results support the development of inhibitors of the mTORC1/2 complexes for the therapy of leukemias that either express BCR/ABL or display deregulation of the PI3K/mTOR signaling pathway.Keywords
This publication has 34 references indexed in Scilit:
- Dual Inhibition of PI3K and mTORC1/2 Signaling by NVP-BEZ235 as a New Therapeutic Strategy for Acute Myeloid LeukemiaClinical Cancer Research, 2010
- From the Bench to the Bed Side: PI3K Pathway Inhibitors in Clinical DevelopmentCurrent Topics in Microbiology and Immunology, 2010
- AZD8055 Is a Potent, Selective, and Orally Bioavailable ATP-Competitive Mammalian Target of Rapamycin Kinase Inhibitor with In vitro and In vivo Antitumor ActivityCancer Research, 2010
- Ku-0063794 is a specific inhibitor of the mammalian target of rapamycin (mTOR)Biochemical Journal, 2009
- Immunoregulatory functions of mTOR inhibitionNature Reviews Immunology, 2009
- Ablation of PI3K blocks BCR-ABL leukemogenesis in mice, and a dual PI3K/mTOR inhibitor prevents expansion of human BCR-ABL+ leukemia cellsJCI Insight, 2008
- The Identification of 2-(1H-Indazol-4-yl)-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (GDC-0941) as a Potent, Selective, Orally Bioavailable Inhibitor of Class I PI3 Kinase for the Treatment of CancerJournal of Medicinal Chemistry, 2008
- Sustained suppression of Bcr-Abl-driven lymphoid leukemia by microRNA mimicsProceedings of the National Academy of Sciences of the United States of America, 2007
- Bcr-Abl kinase modulates the translation regulators ribosomal protein S6 and 4E-BP1 in chronic myelogenous leukemia cells via the mammalian target of rapamycin.2003
- Activity of the Bcr-Abl kinase inhibitor PD180970 against clinically relevant Bcr-Abl isoforms that cause resistance to imatinib mesylate (Gleevec, STI571).2002