Utilizing oxidative stress has recently been regarded as a potential strategy for tumor therapy. The NUAK family SNF1like kinase 1 (NUAK1) is a critical component of the antioxidant defense system and is necessary for the survival of tumors. Therefore, NUAK1 is considered an attractive therapeutic target in cancer. However, antioxidant therapy induced elevated ROS levels to activate the Unc-51-like kinase 1 (ULK1) pathway to promote protective autophagy and ULK1-dependent mitophagy. Thus, the combined inhibition of NUAK1 and ULK1 showed a strong synergistic effect in different tumor types. Herein, the potential antitumor activities of a dual NUAK1/ULK1 inhibitor MRT68921 were evaluated in both tumor cell lines and animal models. MRT68921 significantly kills tumor cells by breaking the balance of oxidative stress signals. These results highlight the potential of MRT68921 as an effective agent for tumor therapy.
S.T. and R.H. managed the patients and wrote the manuscript. Z.G. collected the data. LD revised the manuscript. C.S., X.Z. and C.Y. contributed to patient management. L.Z. produced the figures and Table. Y.H. participated in the registration of the clinical research. J.Y. and Z.L. were responsible for clinical trial recruitment and data revision. J.D. performed flow cytometry detection and bone marrow cell morphology detection. P.C. was responsible for the statistical analysis. Y.S.L. produced CAR T-cells. L.C. designed the study and guided CAR T-cell production. Y.H.L. contributed to the study design and manuscript writing.
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