Sanjiv, K., Calderón-Montaño, J.M., Pham, T.M. et al. (29 more authors) (2021) MTH1 inhibitor TH1579 induces oxidative DNA damage and mitotic arrest in acute myeloid leukemia. Cancer Research, 81 (22). pp. 5733-5744. ISSN 0008-5472
Abstract
Acute myeloid leukemia (AML) is an aggressive hematological malignancy, exhibiting high levels of reactive oxygen species (ROS). ROS levels have been suggested to drive leukemogenesis and is thus a potential novel target for treating AML. MTH1 prevents incorporation of oxidized nucleotides into the DNA to maintain genome integrity and is upregulated in many cancers. Here we demonstrate that hematological cancers are highly sensitive to MTH1 inhibitor TH1579 (karonudib). A functional precision medicine ex vivo screen in primary AML bone marrow samples demonstrated a broad response profile of TH1579, independent of the genomic alteration of AML, resembling the response profile of the standard-of-care treatments cytarabine and doxorubicin. Furthermore, TH1579 killed primary human AML blast cells (CD45+) as well as chemotherapy resistance leukemic stem cells (CD45+Lin-CD34+CD38-),which are often responsible for AML progression. TH1579 killed AML cells by causing mitotic arrest, elevating intracellular ROS levels, and enhancing oxidative DNA damage. TH1579 showed a significant therapeutic window, was well tolerated in animals, and could be combined with standard-of-care treatments to further improve efficacy. TH1579 significantly improved survival in two different AML disease models in vivo. In conclusion, the pre-clinical data presented here support that TH1579 is a promising novel anticancer agent for AML, providing a rational to investigate the clinical usefulness of TH1579 in AML in an on-going clinical phase 1 trial.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2021 The Authors. This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 International (https://creativecommons.org/licenses/by-nc-nd/4.0/). |
Dates: |
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Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 09 Nov 2021 08:48 |
Last Modified: | 24 Nov 2021 08:38 |
Status: | Published |
Publisher: | American Association for Cancer Research (AACR) |
Refereed: | Yes |
Identification Number: | 10.1158/0008-5472.can-21-0061 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:180194 |