Forskning
Udskriv Udskriv
Switch language
Region Hovedstaden - en del af Københavns Universitetshospital
Udgivet

Inhibition of Oxidized Nucleotide Sanitation By TH1579 and Conventional Chemotherapy Cooperatively Enhance Oxidative DNA Damage and Survival in AML

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  1. Acquired Resistance to a MET Antibody Can Be Overcome by the MET Antibody Mixture Sym015

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  2. Proteomics of cancer cell lines resistant to microtubule-stabilizing agents

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  1. TET2 deficiency cooperates with CBFB-MYH11 to induce acute myeloid leukaemia and represents an early leukaemogenic event

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  2. The EHA Research Roadmap: Normal Hematopoiesis

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  3. MTH1 inhibitor TH1579 induces oxidative DNA damage and mitotic arrest in acute myeloid leukemia

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

Vis graf over relationer

Currently, the majority of patients with acute myeloid leukemia (AML) still die of their disease due to primary resistance or relapse toward conventional reactive oxygen species (ROS)- and DNA damage-inducing chemotherapy regimens. Herein, we explored the therapeutic potential to enhance chemotherapy response in AML, by targeting the ROS scavenger enzyme MutT homolog 1 (MTH1, NUDT1), which protects cellular integrity through prevention of fatal chemotherapy-induced oxidative DNA damage. We demonstrate that MTH1 is a potential druggable target expressed by the majority of patients with AML and the inv(16)/KITD816Y AML mouse model mimicking the genetics of patients with AML exhibiting poor response to standard chemotherapy (i.e., anthracycline & cytarabine). Strikingly, combinatorial treatment of inv(16)/KITD816Y AML cells with the MTH1 inhibitor TH1579 and ROS- and DNA damage-inducing standard chemotherapy induced growth arrest and incorporated oxidized nucleotides into DNA leading to significantly increased DNA damage. Consistently, TH1579 and chemotherapy synergistically inhibited growth of clonogenic inv(16)/KITD816Y AML cells without substantially inhibiting normal clonogenic bone marrow cells. In addition, combinatorial treatment of inv(16)/KITD816Y AML mice with TH1579 and chemotherapy significantly reduced AML burden and prolonged survival compared with untreated or single treated mice. In conclusion, our study provides a rationale for future clinical studies combining standard AML chemotherapy with TH1579 to boost standard chemotherapy response in patients with AML. Moreover, other cancer entities treated with ROS- and DNA damage-inducing chemo- or radiotherapies might benefit therapeutically from complementary treatment with TH1579.

OriginalsprogEngelsk
TidsskriftMolecular Cancer Therapeutics
Vol/bind21
Udgave nummer5
Sider (fra-til)703-714
Antal sider12
ISSN1535-7163
DOI
StatusUdgivet - 4 maj 2022

Bibliografisk note

©2022 American Association for Cancer Research.

ID: 77931702