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.
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Acknowledgements
We wish to thank Feiyang Liu for her technical assistance. We thank DiscoveRx Bioscience for performing KinomeScan profiling and the Treespot view image was generated using the web-based TREEspot software (DiscoveRx Biosciences). JDG is supported by NIH grant CA66996. QL and NSG are supported by NIH LINCS Grant HG006097 and R01 CA130876-02.
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JDG has a financial interest with Novartis Pharma AG. JDG and ALK have a financial interest with Novartis Pharma AG. The other authors declare no conflict of interest.
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Weisberg, E., Liu, Q., Nelson, E. et al. Using combination therapy to override stromal-mediated chemoresistance in mutant FLT3-positive AML: synergism between FLT3 inhibitors, dasatinib/multi-targeted inhibitors and JAK inhibitors. Leukemia 26, 2233–2244 (2012). https://doi.org/10.1038/leu.2012.96
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DOI: https://doi.org/10.1038/leu.2012.96
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