Journal
LEUKEMIA
Volume 33, Issue 1, Pages 37-51Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41375-018-0167-0
Keywords
-
Categories
Funding
- Takeda Pharmaceuticals Inc.
- Princess Margaret Cancer Centre Foundation
- Canadian Institutes of Health Research (CIHR)
- Ontario Institute of Cancer Research
- Canada Research Chairs program
- Ontario Ministry of Research and Innovation
- Ministry of Long Term Health and Planning in the Province of Ontario
- Ontario Trillium Scholarship
- GSEF scholarship from the Faculty of Medicine, University of Toronto
- Department of Medical Biophysics fellowship
Ask authors/readers for more resources
Acute myeloid leukemia (AML) is an aggressive hematologic malignancy for which new therapeutic approaches are required. One such potential therapeutic strategy is to target the ubiquitin-like modifier-activating enzyme 1 (UBA1), the initiating enzyme in the ubiquitylation cascade in which proteins are tagged with ubiquitin moieties to regulate their degradation or function. Here, we evaluated TAK-243, a first-in-class UBA1 inhibitor, in preclinical models of AML. In AML cell lines and primary AML samples, TAK-243 induced cell death and inhibited clonogenic growth. In contrast, normal hematopoietic progenitor cells were more resistant. TAK-243 preferentially bound to UBA1 over the related E1 enzymes UBA2, UBA3, and UBA6 in intact AML cells. Inhibition of UBA1 with TAK-243 decreased levels of ubiquitylated proteins, increased markers of proteotoxic stress and DNA damage stress. In vivo, TAK-243 reduced leukemic burden and targeted leukemic stem cells without evidence of toxicity. Finally, we selected populations of AML cells resistant to TAK-243 and identified missense mutations in the adenylation domain of UBA1. Thus, our data demonstrate that TAK-243 targets AML cells and stem cells and support a clinical trial of TAK-243 in this patient population. Moreover, we provide insight into potential mechanisms of acquired resistance to UBA1 inhibitors.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available