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

DOI

10.1158/1541-7786.MCR-22-0343

PMID

36787422

PMCID

PMC11042682

PubMedCentral® Posted Date

4-24-2024

PubMedCentral® Full Text Version

Author MSS

Abstract

Despite effective new therapies, adaptive resistance remains the main obstacle in 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 to 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 pharmacological means, suppresses treatment-induced autophagy, overcomes adaptive drug-resistance, and synergizes with chemotherapy and emerging anti-leukemia agents like venetoclax (ABT-199). The study next aims at exploring the underlying mechanisms. Mechanistically, ULK1 inhibition downregulates MCL1 anti-apoptotic 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.

Keywords

Animals, Mice, Leukemia, Myeloid, Acute, Antineoplastic Agents, Autophagy, Drug Resistance, Neoplasm, Apoptosis, ABT-199 (Venetoclax), Combination therapy, Drug-resistance, Mitochondria, Reactive Oxygen Species (ROS)

Published Open-Access

yes

Recommended Citation

Bhattacharya, Seemana; Piya, Sujan; Ma, Huaxian; et al., "Targeting Unc51-like Autophagy Activating Kinase 1 (ULK1) Overcomes Adaptive Drug Resistance in Acute Myelogenous Leukemia" (2023). Faculty, Staff and Student Publications. 5270.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/5270