Most AML patients exhibit mutational activation of the PI3K/AKT signaling pathway, which promotes downstream effects including growth, survival, DNA repair, and resistance to chemotherapy. Herein we demonstrate that the inv(16)/KITD816Y AML mouse model exhibits constitutive activation of PI3K/AKT signaling, which was enhanced by chemotherapy-induced DNA damage through DNA-PK-dependent AKT phosphorylation. Strikingly, inhibitors of either PI3K or DNA-PK markedly reduced chemotherapy-induced AKT phosphorylation and signaling leading to increased DNA damage and apoptosis of inv(16)/KITD816Y AML cells in response to chemotherapy. Consistently, combinations of chemotherapy and PI3K or DNA-PK inhibitors synergistically inhibited growth and survival of clonogenic AML cells without substantially inhibiting normal clonogenic bone marrow cells. Moreover, treatment of inv(16)/KITD816Y AML mice with combinations of chemotherapy and PI3K or DNA-PK inhibitors significantly prolonged survival compared to untreated/single-treated mice. Mechanistically, our findings implicate that constitutive activation of PI3K/AKT signaling driven by mutant KIT, and potentially other mutational activators such as FLT3 and RAS, cooperates with chemotherapy-induced DNA-PK-dependent activation of AKT to promote survival, DNA repair, and chemotherapy resistance in AML. Hence, our study provides a rationale to select AML patients exhibiting constitutive PI3K/AKT activation for simultaneous treatment with chemotherapy and inhibitors of DNA-PK and PI3K to improve chemotherapy response and clinical outcome.
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The authors thank all bone marrow donors and AML patients, Bente Langelung Kristensen for professional animal care, and colleagues at the FACS Facility at BRIC. This work was supported by a grant from the Danish Cancer Society (ME, R167-A10932-17-S2), KT-M is supported by a clinical research fellowship and a center grant from the Novo Nordisk Foundation (Grant no. 100191, Novo Nordisk Foundation Center for Stem Cell Biology, DanStem; Grant no. NNF17CC0027852, KT-M, BTP). This work was further supported by grants from the Danish Council for Strategic Research (Grant no. 133100153, KT-M), the Danish Cancer Society (Grant no. R72-A4572-13-S2, KT-M), Børnecancerfonden (2016-0255), and Læge Sofus Carl Emil Friis og Hustru Olga Doris Friis Foundation (KT-M), and Tømrermester Jørgen Holm og Hustru Elisa, Brødrene Hartmans Fond, F. Hansen’s Mindelegat (KT-M), and the Intramural Research Program, National Human Genome Research Institute, NIH (LZ and PL).
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Estruch, M., Reckzeh, K., Vittori, C. et al. Targeted inhibition of cooperative mutation- and therapy-induced AKT activation in AML effectively enhances response to chemotherapy. Leukemia (2020). https://doi.org/10.1038/s41375-020-01094-0