Overcoming Wnt-ß-catenin dependent anticancer therapy resistance in leukaemia stem cells.
Nat Cell Biol
; 22(6): 689-700, 2020 06.
Article
em En
| MEDLINE
| ID: mdl-32313104
ABSTRACT
Leukaemia stem cells (LSCs) underlie cancer therapy resistance but targeting these cells remains difficult. The Wnt-ß-catenin and PI3K-Akt pathways cooperate to promote tumorigenesis and resistance to therapy. In a mouse model in which both pathways are activated in stem and progenitor cells, LSCs expanded under chemotherapy-induced stress. Since Akt can activate ß-catenin, inhibiting this interaction might target therapy-resistant LSCs. High-throughput screening identified doxorubicin (DXR) as an inhibitor of the Akt-ß-catenin interaction at low doses. Here we repurposed DXR as a targeted inhibitor rather than a broadly cytotoxic chemotherapy. Targeted DXR reduced Akt-activated ß-catenin levels in chemoresistant LSCs and reduced LSC tumorigenic activity. Mechanistically, ß-catenin binds multiple immune-checkpoint gene loci, and targeted DXR treatment inhibited expression of multiple immune checkpoints specifically in LSCs, including PD-L1, TIM3 and CD24. Overall, LSCs exhibit distinct properties of immune resistance that are reduced by inhibiting Akt-activated ß-catenin. These findings suggest a strategy for overcoming cancer therapy resistance and immune escape.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Células-Tronco Neoplásicas
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Leucemia Mieloide Aguda
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Doxorrubicina
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Resistencia a Medicamentos Antineoplásicos
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PTEN Fosfo-Hidrolase
/
Proteínas Wnt
/
Beta Catenina
Tipo de estudo:
Prognostic_studies
Limite:
Animals
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Female
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Humans
/
Male
Idioma:
En
Revista:
Nat Cell Biol
Ano de publicação:
2020
Tipo de documento:
Article
País de afiliação:
Estados Unidos