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Ferrata Storti Foundation
Haematologica 2022 Volume 107(1):58-76
Targeting MCL-1 dysregulates cell metabo- lism and leukemia-stroma interactions and re-sensitizes acute myeloid leukemia to BCL-2 inhibition
Bing Z. Carter,1 Po Yee Mak,1* Wenjing Tao,1* Marc Warmoes,2 Philip L. Lorenzi,2 Duncan Mak,1 Vivian Ruvolo,1 Lin Tan,2 Justin Cidado,3 Lisa Drew,3 and Michael Andreeff1
1Section of Molecular Hematology & Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX; 2Department of Bioinformatics & Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX and 3Bioscience Oncology R&D, AstraZeneca, Boston, MA, USA
*PYM and WT contributed equally as co-second authors.
ABSTRACT
MCL-1 and BCL-2 are both frequently overexpressed in acute myeloid leukemia (AML) and critical for the survival of AML cells and AML stem cells. MCL-1 is a key factor in venetoclax resistance. Using genetic and pharmacological approaches, we discov- ered that MCL-1 regulates leukemia cell bioenergetics and carbohydrate metabolisms, including the TCA cycle, glycolysis and pentose phos- phate pathway and modulates cell adhesion proteins and leukemia-stro- mal interactions. Inhibition of MCL-1 sensitizes to BCL-2 inhibition in AML cells and AML stem/progenitor cells, including those with intrinsic and acquired resistance to venetoclax through cooperative release of pro-apoptotic BIM, BAX, and BAK from binding to anti-apoptotic BCL- 2 proteins and inhibition of cell metabolism and key stromal microenvi- ronmental mechanisms. The combined inhibition of MCL-1 by MCL-1 inhibitor AZD5991 or CDK9 inhibitor AZD4573 and BCL-2 by veneto- clax greatly extended survival of mice bearing patient-derived xenografts established from an AML patient who acquired resistance to venetoclax/decitabine. These results demonstrate that co-targeting MCL-1 and BCL-2 improves the efficacy of and overcomes pre-existing and acquired resistance to BCL-2 inhibition. Activation of metabolomic pathways and leukemia-stroma interactions are newly discovered func- tions of MCL-1 in AML, which are independent from canonical regula- tion of apoptosis by MCL-1. Our data provide new mechanisms of syn- ergy and a rationale for co-targeting MCL-1 and BCL-2 clinically in patients with AML and potentially other cancers.
Introduction
Acute myeloid leukemia (AML) is a highly heterogeneous and aggressive hema- tological malignancy with dismal treatment outcomes. The survival of AML cells, including stem/progenitor cells, depends on deregulated apoptosis, which partially results from the altered expression of BCL-2 family proteins. Thus, BCL-2 family proteins are promising therapeutic targets in AML.1,2 While combined inhibition of BCL-2 and BCL-XL caused profound thrombocytopenia,3 a highly selective BCL-2 inhibitor, venetoclax, demonstrated potent preclinical activity, but only marginal efficacy in clinical trials in AML.2,4 Conversely, combinations of venetoclax with hypomethylating agents have yielded complete response (CR) or CR with incom- plete cell count recovery rates of >65% in elderly AML patients, but overall sur- vival is only 10 to 17 months due to the development of resistance.5-7
Unlike other BCL-2 proteins, MCL-1 is short-lived and highly regulated at the transcriptional, post-transcriptional, and post-translational levels8 in response to various stimuli. MCL-1 is required for the sustained growth of diverse oncogene-
Acute Myeloid Leukemia
Correspondence:
BING Z. CARTER
bicarter@mdanderson.org
MICHAEL ANDREEFF mandreef@mdanderson.org
Received: May 21, 2020
Accepted: December 14, 2020. Pre-published: December23,2020.
https://doi.org/10.3324/haematol.2020.260331 ©2022 Ferrata Storti Foundation
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