TY - JOUR

T1 - Inhibition of oxidized nucleotide sanitation by TH1579 and conventional chemotherapy cooperatively enhance oxidative DNA-damage and survival in AML

AU - Centio, Anders

AU - Estruch, Montserrat

AU - Reckzeh, Kristian

AU - Sanjiv, Kumar

AU - Vittori, Camilla

AU - Engelhard, Sophia

AU - Warpman Berglund, Ulrika

AU - Helleday, Thomas

AU - Theilgaard-Mönch, Kim

PY - 2022

Y1 - 2022

N2 - Currently, the majority of AML patients still die of their disease due to primary resistance or relapse toward conventional 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 AML patients and the inv(16)/KITD816Y AML mouse model mimicking the genetics of AML patients 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 to 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 AML patients. Moreover, other cancer entities treated with ROS- and DNA damage-inducing chemo- or radiation therapies might benefit therapeutically from complementary treatment with TH1579.

AB - Currently, the majority of AML patients still die of their disease due to primary resistance or relapse toward conventional 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 AML patients and the inv(16)/KITD816Y AML mouse model mimicking the genetics of AML patients 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 to 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 AML patients. Moreover, other cancer entities treated with ROS- and DNA damage-inducing chemo- or radiation therapies might benefit therapeutically from complementary treatment with TH1579.

U2 - 10.1158/1535-7163.MCT-21-0185

DO - 10.1158/1535-7163.MCT-21-0185

M3 - Journal article

C2 - 35247918

SP - 703

EP - 714

JO - Molecular Cancer Therapeutics

JF - Molecular Cancer Therapeutics

SN - 1535-7163

ER -