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Leukemia. 2015 Apr;29(4):828-38. doi: 10.1038/leu.2014.305. Epub 2014 Oct 17.

Dual PI3K/mTOR inhibition shows antileukemic activity in MLL-rearranged acute myeloid leukemia.

Author information

1
1] Department of Internal Medicine III, University Hospital Grosshadern, Ludwig Maximilians University (LMU), Munich, Germany [2] Clinical Cooperative Group Leukemia, Helmholtz Center Munich for Environmental Health, Munich, Germany [3] German Cancer Consortium (DKTK), Heidelberg, Germany [4] German Cancer Research Center (DKFZ), Heidelberg, Germany.
2
1] Department of Internal Medicine III, University Hospital Grosshadern, Ludwig Maximilians University (LMU), Munich, Germany [2] Clinical Cooperative Group Leukemia, Helmholtz Center Munich for Environmental Health, Munich, Germany.
3
Department of Internal Medicine III, University Hospital Grosshadern, Ludwig Maximilians University (LMU), Munich, Germany.
4
Department of Gene Vectors, Helmholtz Center Munich for Environmental Health, Munich, Germany.
5
Department of Translational Oncology, National Center for Tumor Diseases and German Cancer Research Center, Heidelberg, Germany.
6
Center for Human Genetics and Laboratory Medicine, Martinsried, Germany.
7
1] German Cancer Consortium (DKTK), Heidelberg, Germany [2] German Cancer Research Center (DKFZ), Heidelberg, Germany [3] Department of Gene Vectors, Helmholtz Center Munich for Environmental Health, Munich, Germany [4] Department of Oncology, Dr von Haunersches Kinderspital, Ludwig Maximilians University (LMU), Munich, Germany.

Abstract

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.

PMID:
25322685
DOI:
10.1038/leu.2014.305
[Indexed for MEDLINE]

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