MTH1 Inhibitor TH1579 Induces Oxidative DNA Damage and Mitotic Arrest in Acute Myeloid Leukemia.

Abstract

Acute myeloid leukemia (AML) is an aggressive hematologic 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 hematologic 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 preclinical data presented here support that TH1579 is a promising novel anticancer agent for AML, providing a rationale to investigate the clinical usefulness of TH1579 in AML in an ongoing clinical phase I trial. SIGNIFICANCE: The MTH1 inhibitor TH1579 is a potential novel AML treatment, targeting both blasts and the pivotal leukemic stem cells while sparing normal bone marrow cells.

• Authors: Kumar Sanjiv, José Manuel Calderón-Montaño, Therese M Pham, Tom Erkers, Viktoriia Tsuber, Ingrid Almlöf, Andreas Höglund, Yaser Heshmati, Brinton Seashore-Ludlow, Akhilesh Nagesh Danda, Helge Gad, Elisee Wiita, Camilla Göktürk, Azita Rasti, Stefanie Friedrich, Anders Centio, Montserrat Estruch, Thea Kristin Våtsveen, Nona Struyf, Torkild Visnes, Martin Scobie, Tobias Koolmeister, Martin Henriksson, Olov Wallner, Teresa Sandvall, Sören Lehmann, Kim Theilgaard-Mönch, Mathew J Garnett, Päivi Östling, Julian Walfridsson, Thomas Helleday, Ulrika Warpman Berglund
• Journal: Cancer research (Cancer Res) Vol. 81 Issue 22 Pg. 5733-5744 (11 15 2021) ISSN: 1538-7445 [Electronic] United States
• PMID: 34593524 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2021 The Authors; Published by the American Association for Cancer Research.

Chemical References

• Pyrimidines
• Reactive Oxygen Species
• karonudib
• Cytarabine
• Doxorubicin
• Phosphoric Monoester Hydrolases
• 8-oxodGTPase
• DNA Repair Enzymes

Topics

• Animals
• Antineoplastic Combined Chemotherapy Protocols (pharmacology)
• Apoptosis
• Blast Crisis (drug therapy, genetics, metabolism, pathology)
• Cell Proliferation
• Cytarabine (administration & dosage)
• DNA Repair Enzymes (antagonists & inhibitors)
• Doxorubicin (administration & dosage)
• Female
• Gene Expression Regulation, Leukemic (drug effects)
• Humans
• Leukemia, Myeloid, Acute (drug therapy, genetics, metabolism, pathology)
• Mice
• Mice, Inbred NOD
• Mice, SCID
• Mitosis
• Neoplastic Stem Cells (drug effects, metabolism, pathology)
• Phosphoric Monoester Hydrolases (antagonists & inhibitors)
• Prognosis
• Pyrimidines (pharmacology)
• Reactive Oxygen Species (metabolism)
• Tumor Cells, Cultured
• Xenograft Model Antitumor Assays