As examples, protection of AML cells and B-lineage ALL cells from spontaneous and/or drug-induced apoptosis was observed to depend on direct bone marrow fibroblast cell:leukemic cell interaction –. While the significance of stromal-derived growth factors in viability enhancement and cytoprotection of leukemic stem cells cannot be denied, not all hematologic malignancies can be rescued from programmed cell death by secreted cytokines in the absence of direct communication with the stromal cells themselves. Our study also highlighted the potential of Jak inhibitors to synergize with PKC412 and AC220 as well as enhance their apoptotic activity against mutant FLT3-expressing cells cultured in the presence of SCM. We have recently identified the multi-targeted kinase inhibitor, dasatinib, and dasatinib-like compounds as being able to potentiate the activity of TKIs PKC412 and AC220 against mutant FLT3-expressing cells cultured in the presence of cytoprotective and cytokine-abundant stromal-conditioned media (SCM) by performing a combinatorial drug screen using the KIN001 library (Dr. There is thus a need for identification and development of novel therapies that can be effectively combined with TKIs to delay or suppress leukemia progression, override stroma-associated drug resistance, and increase patient survival. In addition, we have found that bone marrow-derived stroma diminishes the activity of both PKC412 and AC220. However, FLT3 inhibitors tested thus far, including PKC412 (midostaurin), which is in late stage (Phase III) clinical trials, and the highly potent and selective FLT3 inhibitor, AC220 (quizartinib), which is in early phase clinical trials, generally at best induce partial and transient clinical responses in patients when used alone. Ī subset of AML cells expresses a mutated form of the class III receptor tyrosine kinase FLT3 ( Fms- Like Tyrosine kinase-3 STK-1, human Stem Cell Tyrosine Kinase-1 or FLK-2, Fetal Liver Kinase-2), which has inspired the development of a number of small molecule inhibitors of mutant FLT3. Of relevance, we have found that media conditioned by human HS-5 stromal cells, as well as a cocktail of cytokines secreted in high concentrations by HS-5 stroma (including SCF, IL-6, IL-8, IL-11, M-CSF and GM-CSF), were able to partially protect TKI-treated chronic myeloid leukemia (CML) cells and AML cells.
Indeed, the number of existing leukemic stem cells that exhibit high survival ability on bone marrow stromal layers has proven to be a significant prognostic indicator. As small numbers of leukemia cells have been observed to persist in the bone marrow of TKI-treated patients, despite rapid and dramatic clearance of peripheral blood blasts, there is growing interest in determining the role of the bone marrow microenvironment in the long-term survival of leukemic stem cells. Resistance to TKIs in leukemia patients presents a significant clinical challenge. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Ĭompeting interests: JDG has a financial interest with Novartis Pharma AG. FL is supported by a Chinese Academy of Science High Magnetic Field Laboratory training grant.
This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.įunding: Grant Support: QL and NG are supported by National Institutes of Health (NIH) Library of Integrated Network-Based Cellular Signatures (LINCS) grant HG006097. Received: NovemAccepted: JanuPublished: February 21, 2013Ĭopyright: © 2013 Weisberg et al. Institut national de la santé et de la recherche médicale (INSERM), France (2013) Selective Akt Inhibitors Synergize with Tyrosine Kinase Inhibitors and Effectively Override Stroma-Associated Cytoprotection of Mutant FLT3-Positive AML Cells.
Citation: Weisberg E, Liu Q, Zhang X, Nelson E, Sattler M, Liu F, et al.