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

Morrish, E; Copeland, A; Moujalled, DM; Powell, JA; Silke, N; Lin, A; Jarman, KE; Sandow, JJ; Ebert, G; Mackiewicz, L; Beach, JA; Christie, EL; Lewis, AC; Pomilio, G; Fischer, KC; MacPherson, L; Bowtell, DDL; Webb, AI; Pellegrini, M; Dawson, MA; Pitson, SM; Wei, AH; Silke, J; Brumatti, G

Author(s): Morrish, E; Copeland, A; Moujalled, DM; Powell, JA; Silke, N; Lin, A; Jarman, KE; Sandow, JJ; Ebert, G; Mackiewicz, L; Beach, JA; Christie, EL; Lewis, AC; Pomilio, G; Fischer, KC; MacPherson, L; Bowtell, DDL; Webb, AI; Pellegrini, M; Dawson, MA; Pitson, SM; Wei, AH; Silke, J; Brumatti, G;
Details: Publication Year 2020-10-27,Volume 4,Issue #20,Page 5062-5077
Journal Title: Blood Advances
Publication Type: Journal Article
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.
Publisher: ASH
Research Division(s): Blood Cells And Blood Cancer; Inflammation; Advanced Technology And Biology; Infectious Diseases And Immune Defence
PubMed ID: 33080008
Publisher's Version: https://doi.org/10.1182/bloodadvances.2020001576
Open Access at Publisher's Site: https://doi.org/10.1182/bloodadvances.2020001576
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2021-02-01 12:05:24

Last Modified: 2021-03-02 10:54:31