Abstract
Abstract The PI3K/AKT/mTOR and Raf/MEK/ERK pathways, resulting in increased levels of Mcl-1, XIAP and survivin, have been found to be activated in acute myeloid leukemia cells (AML) due to the mutant receptor tyrosine kinases. FMS-like tyrosine kinase (FLT3) mutations including FLT3-internal tandem duplication (FLT3-ITD) are found in about 30% of cases of acute myeloid leukemia and confer an increased relapse rate and reduced overall survival. Sorafenib, inhibiting Raf-1 of the MAPK pathway resulting in diminished MEK and ERK phosphorylation, is being tested in AML patients with FLT3-ITD and modest responses have been observed: similarly flavopiridol, a CDK and mRNA transcription inhibitor, has been tested in AML patients with some evidence of activity. We hypothesize that sorafenib plus flavopiridol will have enhanced therapeutic effects. The combined apoptotic effects of sorafenib plus flavopiridol were investigated in HL-60, MV4;11 FLT3-ITD+ cells, as well as in primary leukemic cells isolated from AML patients. Sorafenib and flavopiridol indepedently induced apoptosis at 10 μM and 200 nM, respectively, in HL-60 cells which was correlated with the down-regulation of Mcl-1, XIAP and/or survivin. The combination of sorafenib (5 μM) plus flavopiridol (100 nM) produced augmented apoptosis associated with enhanced diminution in levels of Mcl-1. MV4;11 cells were more sensitive than HL-60 cells to sorafenib-induced apoptosis, but not to flavopiridol, with the down-regulation of Mcl-1 and survivin. Addition of flavopiridol to MV4;11 cells enhanced sorafenib-induced apoptosis with augmented down-regulation of XIAP. Primary cells isolated from two AML patients with FLT3-ITD+ cells exhibited augmented apoptosis induction with the combination treatment of sorafenib plus flavopiridol. Our data suggest that the augmented apoptosis induction in AML cells by sorafenib plus flavopiridol is mediated by decreasing levels of complimentary anti-apoptotic proteins. This novel combination therapy is worthy of a clinical trial in FLT3-ITD+ AML patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3501. doi:10.1158/1538-7445.AM2011-3501
Published Version
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