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Sandhöfer, N. ; Metzeler, K.H. ; Carlet, M. ; Dufour, A.* ; Fröhling, S.* ; Groiß, V. ; Grunert, M. ; Herold, T. ; Hinrichsen, T.* ; Hiddemann, W. ; Klein, H.G.* ; Rothenburg, M.* ; Schneider, S.* ; Subklewe, M. ; Tiedt, S. ; Wachter, O.* ; Walter, G.* ; Jeremias, I. ; Spiekermann, K.

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

Leukemia 29, 828-838 (2015)
DOI PMC
Open Access Green as soon as Postprint is submitted to ZB.
In acute myeloid leukemia (AML), several signaling pathways such as the 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 hours 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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Publication type Article: Journal article
Document type Scientific Article
Keywords Acute Myelogenous Leukemia; Nf-kappa-b; Hematopoietic Stem-cells; Constitutive Phosphorylation; Mek Inhibition; Breast-cancer; Aml; Mutations; Rapamycin; Target
ISSN (print) / ISBN 0887-6924
e-ISSN 1476-5551
Journal Leukemia
Quellenangaben Volume: 29, Issue: 4, Pages: 828-838 Article Number: , Supplement: ,
Publisher Nature Publishing Group
Publishing Place London
Reviewing status Peer reviewed
Institute(s) Research Unit Gene Vector (AGV)
CCG Pathogenesis of Acute Myeloid Leukemia (KKG-KPL)
CCG Hematopoetic Cell Transplants (IMI-KHZ)