Targeting Unc51-like Autophagy Activating Kinase 1 (ULK1) Overcomes Adaptive Drug Resistance in Acute Myelogenous Leukemia

Authors

Seemana Bhattacharya
Sujan Piya
Huaxian Ma
Priyanka Sharma
Qi Zhang
Natalia Baran
Vivian R Ruvolo
Teresa McQueen
R Eric Davis
Rasoul Pourebrahim
Marina Konopleva
Hagop Kantarjian
Nicholas D P Cosford
Michael Andreeff
Gautam Borthakur

Publication Date

6-1-2023

Journal

Molecular Cancer Research

Abstract

UNLABELLED: 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, DNA damage, 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, in the 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.

Keywords

Animals, Mice, Leukemia, Myeloid, Acute, Antineoplastic Agents, Autophagy, Drug Resistance, Neoplasm, Apoptosis

Comments

Supplementary Materials

PMID: 36787422