Clinical MDR1 inhibitors enhance Smac-mimetic bioavailability to kill murine LSCs and improve survival in AML models
AuthorMorrish, E; Copeland, A; Moujalled, DM; Powell, JA; Silke, N; Lin, A; Jarman, KE; Sandow, JJ; Ebert, G; Mackiewicz, L; ...
Source TitleBlood Advances
PublisherAMER SOC HEMATOLOGY
University of Melbourne Author/sSandow, Jarrod; Ebert, Gregor; Brumatti, Gabriela; Silke, John; Morrish, Emma; Jarman, Kate; Pellegrini, Marc
AffiliationMedical Biology (W.E.H.I.)
Document TypeJournal Article
CitationsMorrish, E., Copeland, A., Moujalled, D. M., Powell, J. A., Silke, N., Lin, A., Jarman, K. E., Sandow, J. J., Ebert, G., Mackiewicz, L., Beach, J. A., Christie, E. L., Lewis, A. C., Pomilio, G., Fischer, K. C., MacPherson, L., Bowtell, D. D. L., Webb, A., Pellegrini, M. ,... Brumatti, G. (2020). Clinical MDR1 inhibitors enhance Smac-mimetic bioavailability to kill murine LSCs and improve survival in AML models. BLOOD ADVANCES, 4 (20), pp.5062-5077. https://doi.org/10.1182/bloodadvances.2020001576.
Access StatusAccess this item via the Open Access location
Open Access URLPublished version
The specific targeting of inhibitor of apoptosis (IAP) proteins by Smac-mimetic (SM) drugs, such as birinapant, has been tested in clinical trials of acute myeloid leukemia (AML) and certain solid cancers. Despite their promising safety profile, SMs have had variable and limited success. Using a library of more than 5700 bioactive compounds, we screened for approaches that could sensitize AML cells to birinapant and identified multidrug resistance protein 1 inhibitors (MDR1i) as a class of clinically approved drugs that can enhance the efficacy of SM therapy. Genetic or pharmacological inhibition of MDR1 increased intracellular levels of birinapant and sensitized AML cells from leukemia murine models, human leukemia cell lines, and primary AML samples to killing by birinapant. The combination of clinical MDR1 and IAP inhibitors was well tolerated in vivo and more effective against leukemic cells, compared with normal hematopoietic progenitors. Importantly, birinapant combined with third-generation MDR1i effectively killed murine leukemic stem cells (LSCs) and prolonged survival of AML-burdened mice, suggesting a therapeutic opportunity for AML. This study identified a drug combination strategy that, by efficiently killing LSCs, may have the potential to improve outcomes in patients with AML.
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