Dual PI3K/mTOR inhibition shows antileukemic activity in MLL-rearranged acute myeloid leukemia
In acute myeloid leukemia (AML), several signaling pathways such as the phosphatidylinositol-3-kinase/AKT and the mammalian target of rapamycin (PI3K/AKT/mTOR) pathway are deregulated and constitutively activated as a consequence of genetic and cytogenetic abnormalities. We tested the effectiveness...
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| Main Authors: | , , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
2015
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| In: |
Leukemia
Year: 2015, Volume: 29, Issue: 4, Pages: 828-838 |
| ISSN: | 1476-5551 |
| DOI: | 10.1038/leu.2014.305 |
| Online Access: | Verlag, Volltext: http://dx.doi.org/10.1038/leu.2014.305 Verlag, Volltext: https://www.nature.com/leu/journal/v29/n4/full/leu2014305a.html 
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| Author Notes: | N. Sandhöfer, K.H. Metzeler, M. Rothenberg, T. Herold, S. Tiedt, V. Groiß, M. Carlet, G. Walter, T. Hinrichsen, O. Wachter, M. Grunert, S. Schneider, M. Subklewe, A. Dufour, S. Fröhling, H.-G. Klein, W. Hiddemann, I. Jeremias and K. Spiekermann |
| Summary: | In acute myeloid leukemia (AML), several signaling pathways such as the phosphatidylinositol-3-kinase/AKT and the mammalian target of rapamycin (PI3K/AKT/mTOR) pathway are deregulated and constitutively activated as a consequence of genetic and cytogenetic abnormalities. We tested the effectiveness of PI3K/AKT/mTOR-targeting therapies and tried to identify alterations that associate with treatment sensitivity. By analyzing primary samples and cell lines, we observed a wide range of cytotoxic activity for inhibition of AKT (MK-2206), mTORC1 (rapamycin) and PI3K/mTORC1/2 (BEZ-235) with a high sensitivity of cells carrying an MLL rearrangement. In vivo PI3K/mTOR inhibition delayed tumor progression, reduced tumor load and prolonged survival in an MLL-AF9+/FLT3-ITD+ xenograft mouse model. By performing targeted amplicon sequencing in 38 MLL-AF9+ and 125 cytogenetically normal AML patient samples, we found a high additional mutation rate for genes involved in growth factor signaling in 79% of all MLL-AF9+ samples, which could lead to a possible benefit of this cohort. PI3K/mTOR inhibition for 24 h led to the cross-activation of the ERK pathway. Further in vitro studies combining PI3K/mTOR and ERK pathway inhibition revealed highly synergistic effects in apoptosis assays. Our data implicate a possible therapeutic benefit of PI3K/mTOR inhibition in the MLL-mutated subgroup. Inhibiting rescue pathways could improve the therapeutic efficacy of PI3K-targeted therapies in AML. |
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| Item Description: | published online 21 November 2014 Gesehen am 25.07.2017 |
| Physical Description: | Online Resource |
| ISSN: | 1476-5551 |
| DOI: | 10.1038/leu.2014.305 |