TY - JOUR
T1 - Targeting Unc51-like Autophagy Activating Kinase 1 (ULK1) Overcomes Adaptive Drug Resistance in Acute Myelogenous Leukemia
AU - Bhattacharya, Seemana
AU - Piya, Sujan
AU - Ma, Huaxian
AU - Sharma, Priyanka
AU - Zhang, Qi
AU - Baran, Natalia
AU - Ruvolo, Vivian R.
AU - McQueen, Teresa
AU - Eric Davis, R.
AU - Pourebrahim, Rasoul
AU - Konopleva, Marina
AU - Kantarjian, Hagop
AU - Cosford, Nicholas D.P.
AU - Andreeff, Michael
AU - Borthakur, Gautam
N1 - Publisher Copyright:
© 2023 American Association for Cancer Research Inc.. All rights reserved.
PY - 2023/6
Y1 - 2023/6
N2 - Despite effective new therapies, adaptive resistance remains the main obstacle in acute myelogenous leukemia (AML) therapy. Autophagy induction is a key mechanism for adaptive resistance. Leukemic blasts at diagnosis express higher levels of the apical autophagy kinase ULK1 compared with normal hematopoietic cells. Exposure to chemotherapy and targeted agents upregulate ULK1, hence we hypothesize that developing ULK1 inhibitors may present the unique opportunity for clinical translation of autophagy inhibition. Accordingly, we demonstrate that ULK1 inhibition, by genetic and pharmacologic means, suppresses treatment-induced autophagy, overcomes adaptive drug-resistance, and synergizes with chemotherapy and emerging antileukemia agents like venetoclax (ABT-199). The study next aims at exploring the underlying mechanisms. Mechanistically, ULK1 inhibition downregulates MCL1 antiapoptotic gene, impairs mitochondrial function and downregulates components of the CD44-xCT system, resulting in impaired reactive oxygen species (ROS)mitigation,DNAdamage, and apoptosis. For further validation, several mouse models of AML were generated. In these mouse models, ULK1 deficiency impaired leukemic cell homing and engraftment, delayed disease progression, and improved survival.Therefore, inthe study,we validated our hypothesis and identified ULK1 as an important mediator of adaptive resistance to therapy and an ideal candidate for combination therapy in AML. Therefore, we propose ULK1 inhibition as a therapeutically relevant treatment option to overcome adaptive drug-resistance in AML. Implications: ULK1 drives a cell-intrinsic adaptive resistance in AML and targeting ULK1-mediated autophagy can synergize with existing and emerging AML therapies to overcome drug-resistance and induce apoptosis.
AB - Despite effective new therapies, adaptive resistance remains the main obstacle in acute myelogenous leukemia (AML) therapy. Autophagy induction is a key mechanism for adaptive resistance. Leukemic blasts at diagnosis express higher levels of the apical autophagy kinase ULK1 compared with normal hematopoietic cells. Exposure to chemotherapy and targeted agents upregulate ULK1, hence we hypothesize that developing ULK1 inhibitors may present the unique opportunity for clinical translation of autophagy inhibition. Accordingly, we demonstrate that ULK1 inhibition, by genetic and pharmacologic means, suppresses treatment-induced autophagy, overcomes adaptive drug-resistance, and synergizes with chemotherapy and emerging antileukemia agents like venetoclax (ABT-199). The study next aims at exploring the underlying mechanisms. Mechanistically, ULK1 inhibition downregulates MCL1 antiapoptotic gene, impairs mitochondrial function and downregulates components of the CD44-xCT system, resulting in impaired reactive oxygen species (ROS)mitigation,DNAdamage, and apoptosis. For further validation, several mouse models of AML were generated. In these mouse models, ULK1 deficiency impaired leukemic cell homing and engraftment, delayed disease progression, and improved survival.Therefore, inthe study,we validated our hypothesis and identified ULK1 as an important mediator of adaptive resistance to therapy and an ideal candidate for combination therapy in AML. Therefore, we propose ULK1 inhibition as a therapeutically relevant treatment option to overcome adaptive drug-resistance in AML. Implications: ULK1 drives a cell-intrinsic adaptive resistance in AML and targeting ULK1-mediated autophagy can synergize with existing and emerging AML therapies to overcome drug-resistance and induce apoptosis.
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U2 - 10.1158/1541-7786.MCR-22-0343
DO - 10.1158/1541-7786.MCR-22-0343
M3 - Article
C2 - 36787422
AN - SCOPUS:85160965739
SN - 1541-7786
VL - 21
SP - 548
EP - 563
JO - Molecular Cancer Research
JF - Molecular Cancer Research
IS - 6
ER -