Journal article

Clinical MDR1 inhibitors enhance Smac-mimetic bioavailability to kill murine LSCs and improve survival in AML models

Emma Morrish, Anthony Copeland, Donia M Moujalled, Jason A Powell, Natasha Silke, Ann Lin, Kate E Jarman, Jarrod J Sandow, Gregor Ebert, Liana Mackiewicz, Jessica A Beach, Elizabeth L Christie, Alexander C Lewis, Giovanna Pomilio, Karla C Fischer, Laura MacPherson, David DL Bowtell, Andrew Webb, Marc Pellegrini, Mark A Dawson Show all

BLOOD ADVANCES | AMER SOC HEMATOLOGY | Published : 2020

Abstract

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 muri..

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Grants

Awarded by Leukemia & Lymphoma Society (SCOR [Specialized Centre of Research]) grant


Awarded by National Health and Medical Research Council (NHMRC)


Awarded by Cancer Australia


Awarded by Leukaemia Foundation Australia priority grant PdCCRS


Awarded by NHMRC fellowship


Awarded by Victoria Cancer Agency (VCA) mid-career fellowship MCRF


Awarded by Australian Government NHMRC Independent Research Institutes Infrastructure Support Scheme (IRIISS) grant


Funding Acknowledgements

This work was supported by Leukemia & Lymphoma Society (SCOR [Specialized Centre of Research]) grant 7015-18 (J.S.); National Health and Medical Research Council (NHMRC) grants 1025594, 1046010, and 1081376; Cancer Australia and Leukaemia Foundation Australia priority grant PdCCRS 1162023 (G.B.); NHMRC fellowship 1107149 (J.S.); Victoria Cancer Agency (VCA) mid-career fellowship MCRF 15027 (G.B.); and Australian Cancer Research Foundation and Victorian State Government Operational Infrastructure Support and Australian Government NHMRC Independent Research Institutes Infrastructure Support Scheme (IRIISS) grant 9000433.