ULK1 inhibition promotes oxidative stress-induced differentiation and sensitizes leukemic stem cells to targeted therapy.
Sci Transl Med
; 13(613): eabd5016, 2021 Sep 29.
Article
em En
| MEDLINE
| ID: mdl-34586834
ABSTRACT
Inhibition of autophagy has been proposed as a potential therapy for individuals with cancer. However, current lysosomotropic autophagy inhibitors have demonstrated limited efficacy in clinical trials. Therefore, validation of novel specific autophagy inhibitors using robust preclinical models is critical. In chronic myeloid leukemia (CML), minimal residual disease is maintained by persistent leukemic stem cells (LSCs), which drive tyrosine kinase inhibitor (TKI) resistance and patient relapse. Here, we show that deletion of autophagy-inducing kinase ULK1 (unc-51like autophagy activating kinase 1) reduces growth of cell line and patient-derived xenografted CML cells in mouse models. Using primitive cells, isolated from individuals with CML, we demonstrate that pharmacological inhibition of ULK1 selectively targets CML LSCs ex vivo and in vivo, when combined with TKI treatment. The enhanced TKI sensitivity after ULK1-mediated autophagy inhibition is driven by increased mitochondrial respiration and loss of quiescence and points to oxidative stressinduced differentiation of CML LSCs, proposing an alternative strategy for treating patients with CML.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Autofagia
/
Estresse Oxidativo
Idioma:
En
Ano de publicação:
2021
Tipo de documento:
Article