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

• Verfasst von: Sandhöfer, Nadine [VerfasserIn]
• Verfasst von: Walter, Gina J. [VerfasserIn]
• Verfasst von: Fröhling, Stefan [VerfasserIn]
• Titel: Dual PI3K/mTOR inhibition shows antileukemic activity in MLL-rearranged acute myeloid leukemia
• Verf.angabe: 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
• Umfang: 11 S.
• Fussnoten: published online 21 November 2014 ; Gesehen am 25.07.2017
• Titel Quelle: Enthalten in: Leukemia
• Jahr Quelle: 2015
• Band/Heft Quelle: 29(2015), 4, S. 828-838
• ISSN Quelle: 1476-5551
• DOI: doi:10.1038/leu.2014.305
• Datenträger: Online-Ressource
• Sprache: eng
• K10plus-PPN: 1561187003

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.