2. Academic Validation
  3. Clinical MDR1 inhibitors enhance Smac-mimetic bioavailability to kill murine LSCs and improve survival in AML models

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

  • Blood Adv. 2020 Oct 27;4(20):5062-5077. doi: 10.1182/bloodadvances.2020001576.
Emma Morrish 1 2,  Anthony Copeland 1 2,  Donia M Moujalled 3 4,  Jason A Powell 5 6,  Natasha Silke 1,  Ann Lin 1,  Kate E Jarman 1 2,  Jarrod J Sandow 1 2,  Gregor Ebert 1 2,  Liana Mackiewicz 1,  Jessica A Beach 7 8,  Elizabeth L Christie 7 8,  Alexander C Lewis 5,  Giovanna Pomilio 3 4,  Karla C Fischer 1 2,  Laura MacPherson 7 8,  David D L Bowtell 7 8,  Andrew I Webb 1 2,  Marc Pellegrini 1 2,  Mark A Dawson 7 8,  Stuart M Pitson 5 6,  Andrew H Wei 3 4,  John Silke 1 2,  Gabriela Brumatti 1 2
Affiliations

Affiliations

  • 1 Inflammation Division, Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia.
  • 2 Department of Medical Biology, University of Melbourne, Melbourne, VIC, Australia.
  • 3 Australian Centre for Blood Diseases, Monash University, Melbourne, VIC, Australia.
  • 4 Department of Clinical Haematology, The Alfred Hospital, Melbourne, VIC, Australia.
  • 5 Molecular Signalling Laboratory, Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, SA, Australia.
  • 6 Adelaide Medical School, University of Adelaide, Adelaide SA, Australia.
  • 7 Peter MacCallum Cancer Centre, Melbourne, VIC Australia; and.
  • 8 Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia.
PMID: 33080008 DOI: 10.1182/bloodadvances.2020001576
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 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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