2. Academic Validation
  3. Blockade of ROS production inhibits oncogenic signaling in acute myeloid leukemia and amplifies response to precision therapies

Blockade of ROS production inhibits oncogenic signaling in acute myeloid leukemia and amplifies response to precision therapies

  • Sci Signal. 2023 Mar 28;16(778):eabp9586. doi: 10.1126/scisignal.abp9586.
Zacary P Germon 1 2,  Jonathan R Sillar 1 2 3,  Abdul Mannan 1 2,  Ryan J Duchatel 1 2,  Dilana Staudt 1 2,  Heather C Murray 1 2,  Izac J Findlay 1 2,  Evangeline R Jackson 1 2,  Holly P McEwen 1 2,  Alicia M Douglas 1 2,  Tabitha McLachlan 1 2,  John E Schjenken 4,  David A Skerrett-Byrne 4,  Honggang Huang 5,  Marcella N Melo-Braga 5 6,  Maximilian W Plank 1 7,  Frank Alvaro 2 8,  Janis Chamberlain 2 8,  Geoff De Iuliis 4,  R John Aitken 4,  Brett Nixon 4,  Andrew H Wei 9,  Anoop K Enjeti 1 2 3 10,  Yizhou Huang 11,  Richard B Lock 11,  Martin R Larsen 5,  Heather Lee 1 2,  Vijesh Vaghjiani 12 13,  Jason E Cain 12 13,  Charles E de Bock 11,  Nicole M Verrills 1 2,  Matthew D Dun 1 2
Affiliations

Affiliations

  • 1 Cancer Signalling Research Group, School of Biomedical Sciences and Pharmacy, College of Health, Medicine and Wellbeing, University of Newcastle, Callaghan, NSW, Australia.
  • 2 Precision Medicine Research Program, Hunter Medical Research Institute, New Lambton Heights, NSW, Australia.
  • 3 Department of Haematology, Calvary Mater Hospital, Waratah, NSW, Australia.
  • 4 Priority Research Centre for Reproductive Science, School of Environmental and Life Sciences, College of Engineering, Science and Environment, University of Newcastle, Callaghan, NSW, Australia.
  • 5 Department of Molecular Biology and Biochemistry, Protein Research Group, University of Southern Denmark, Odense, Denmark.
  • 6 Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
  • 7 GlaxoSmithKline, Abbotsford, Victoria, Australia.
  • 8 John Hunter Children's Hospital, New Lambton Heights, NSW, Australia.
  • 9 Australian Centre for Blood Diseases, Monash University, Melbourne, VIC, Australia.
  • 10 NSW Health Pathology, John Hunter Hospital, New Lambton Heights, NSW, Australia.
  • 11 Children's Cancer Institute, Lowy Cancer Centre, School of Women's and Children's Health, University of New South Wales Centre for Childhood Cancer Research, UNSW Sydney, Kensington, NSW, Australia.
  • 12 Centre for Cancer Research, Hudson Institute of Medical Research, Clayton, VIC, Australia.
  • 13 Department of Molecular and Translational Science, Monash University, Clayton, VIC, Australia.
PMID: 36976863 DOI: 10.1126/scisignal.abp9586
Abstract

Mutations in the type III receptor tyrosine kinase FLT3 are frequent in patients with acute myeloid leukemia (AML) and are associated with a poor prognosis. AML is characterized by the overproduction of Reactive Oxygen Species (ROS), which can induce cysteine oxidation in redox-sensitive signaling proteins. Here, we sought to characterize the specific pathways affected by ROS in AML by assessing oncogenic signaling in primary AML samples. The oxidation or phosphorylation of signaling proteins that mediate growth and proliferation was increased in samples from patient subtypes with FLT3 mutations. These samples also showed increases in the oxidation of proteins in the ROS-producing Rac/NADPH oxidase-2 (NOX2) complex. Inhibition of NOX2 increased the Apoptosis of FLT3-mutant AML cells in response to FLT3 inhibitors. NOX2 inhibition also reduced the phosphorylation and cysteine oxidation of FLT3 in patient-derived xenograft mouse models, suggesting that decreased oxidative stress reduces the oncogenic signaling of FLT3. In mice grafted with FLT3 mutant AML cells, treatment with a NOX2 Inhibitor reduced the number of circulating Cancer cells, and combining FLT3 and NOX2 inhibitors increased survival to a greater extent than either treatment alone. Together, these data raise the possibility that combining NOX2 and FLT3 inhibitors could improve the treatment of FLT3 mutant AML.

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