Using combination therapy to override stromal-mediated chemoresistance in mutant FLT3-positive AML: synergism between FLT3 inhibitors, dasatinib/multi-targeted inhibitors and JAK inhibitors

Title
Using combination therapy to override stromal-mediated chemoresistance in mutant FLT3-positive AML: synergism between FLT3 inhibitors, dasatinib/multi-targeted inhibitors and JAK inhibitors
Authors
E WeisbergQ LiuErik NelsonA L KungA L ChristieR BronsonM SattlerT SandaZ Zhao허우영C MitsiadesR SmithJF DaleyR StoneI GalinskyJD GriffinN Gray
Keywords
acute myeloid leukemia; multi-targeted kinase inhibitor; PKC412; AC220; stromal-mediated chemoresistance; synergy
Issue Date
2012-04
Publisher
Leukemia : official journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Citation
VOL 26, 2233-2244
Abstract
Acute myeloid leukemia (AML) progenitors are frequently characterized by activating mutations in the receptor tyrosine kinase Fms-like tyrosine kinase-3 (FLT3). Protein tyrosine kinases are integral components of signaling cascades that have a role in both FLT3-mediated transformation as well as viability pathways that are advantageous to leukemic cell survival. The bone marrow microenvironment can diminish AML sensitivity to tyrosine kinase inhibitors. We hypothesized that inhibition of protein kinases in addition to FLT3 may be effective in overriding drug resistance in AML. We used a cell-based model mimicking stromal protection as part of an unbiased high-throughput chemical screen to identify kinase inhibitors with the potential to override microenvironment-mediated drug resistance in mutant FLT3-positive AML. Several related multi-targeted kinase inhibitors, including dasatinib, with the capability of reversing microenvironment-induced resistance to FLT3 inhibition were identified and validated. We validated synergy in vitro and demonstrated effective combination potential in vivo. In particular Janus kinase inhibitors were effective in overriding stromal protection and potentiating FLT3 inhibition in primary AML and cell lines. These results hint at a novel concept of using combination therapy to override drug resistance in mutant FLT3-positive AML in the bone marrow niche and suppress or eradicate residual disease.
URI
http://pubs.kist.re.kr/handle/201004/49738
ISSN
08876924
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KIST Publication > Article
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