MTH1 Inhibitor TH1579 Induces Oxidative DNA Damage and Mitotic Arrest in Acute Myeloid Leukemia
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MTH1 Inhibitor TH1579 Induces Oxidative DNA Damage and Mitotic Arrest in Acute Myeloid Leukemia. / Sanjiv, Kumar; Calderón-Montaño, José Manuel; Pham, Therese M; Erkers, Tom; Tsuber, Viktoriia; Almlöf, Ingrid; Höglund, Andreas; Heshmati, Yaser; Seashore-Ludlow, Brinton; Nagesh Danda, Akhilesh; Gad, Helge; Wiita, Elisee; Göktürk, Camilla; Rasti, Azita; Friedrich, Stefanie; Centio, Anders; Estruch, Montserrat; Våtsveen, Thea Kristin; Struyf, Nona; Visnes, Torkild; Scobie, Martin; Koolmeister, Tobias; Henriksson, Martin; Wallner, Olov; Sandvall, Teresa; Lehmann, Sören; Theilgaard-Mönch, Kim; Garnett, Mathew J; Östling, Päivi; Walfridsson, Julian; Helleday, Thomas; Warpman Berglund, Ulrika.
I: Cancer Research, Bind 81, Nr. 22, 2021, s. 5733-5744.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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TY - JOUR
T1 - MTH1 Inhibitor TH1579 Induces Oxidative DNA Damage and Mitotic Arrest in Acute Myeloid Leukemia
AU - Sanjiv, Kumar
AU - Calderón-Montaño, José Manuel
AU - Pham, Therese M
AU - Erkers, Tom
AU - Tsuber, Viktoriia
AU - Almlöf, Ingrid
AU - Höglund, Andreas
AU - Heshmati, Yaser
AU - Seashore-Ludlow, Brinton
AU - Nagesh Danda, Akhilesh
AU - Gad, Helge
AU - Wiita, Elisee
AU - Göktürk, Camilla
AU - Rasti, Azita
AU - Friedrich, Stefanie
AU - Centio, Anders
AU - Estruch, Montserrat
AU - Våtsveen, Thea Kristin
AU - Struyf, Nona
AU - Visnes, Torkild
AU - Scobie, Martin
AU - Koolmeister, Tobias
AU - Henriksson, Martin
AU - Wallner, Olov
AU - Sandvall, Teresa
AU - Lehmann, Sören
AU - Theilgaard-Mönch, Kim
AU - Garnett, Mathew J
AU - Östling, Päivi
AU - Walfridsson, Julian
AU - Helleday, Thomas
AU - Warpman Berglund, Ulrika
PY - 2021
Y1 - 2021
N2 - 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.
AB - 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.
U2 - 10.1158/0008-5472.CAN-21-0061
DO - 10.1158/0008-5472.CAN-21-0061
M3 - Journal article
C2 - 34593524
VL - 81
SP - 5733
EP - 5744
JO - Cancer Research
JF - Cancer Research
SN - 0008-5472
IS - 22
ER -
ID: 281945916