Inducible SHP-2 activation confers resistance to imatinib in drug-tolerant chronic myeloid leukemia cells.
Toxicol Appl Pharmacol
; 360: 249-256, 2018 12 01.
Article
en En
| MEDLINE
| ID: mdl-30290167
ABSTRACT
BCR-ABL kinase mutations, accounting for clinical resistance to tyrosine kinase inhibitor (TKI) such as imatinib, frequently occur in acquired resistance or in advanced phases of chronic myeloid leukemia (CML). Emerging evidence implicates a critical role for non-mutational drug resistance mechanisms underlying the survival of residual cancer 'persister' cells. Here, we utilized non-mutational imatinib-resistant K562/G cells to reveal SHP-2 as a resistance modulator of imatinib treatment response during the early phase. SHP-2 phosphorylation was significantly higher in K562/G cells than in sensitive K562 cells. In K562 cells, both short-term and long-term exposure to imatinib induced SHP-2 phosphorylation. Consistently, gain- and loss-of-function mutants in SHP-2 proved its regulation of imatinib resistance. SHP-2 inhibitor and imatinib exhibited a strong antitumor synergy in in vitro and in vivo K562/G models. Mechanistically, dual SHP-2 and BCR-ABL inhibition blocked RAF/MEK/ERK and PI3K/AKT/mTOR pathways, respectively, leading to dramatic apoptotic death of K562/G cells. In conclusion, our results highlight that SHP-2 could be exploited as a biomarker and therapeutic target during the early phase of imatinib resistance development in CML.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Leucemia Mielógena Crónica BCR-ABL Positiva
/
Resistencia a Antineoplásicos
/
Inhibidores de Proteínas Quinasas
/
Proteína Tirosina Fosfatasa no Receptora Tipo 11
/
Mesilato de Imatinib
Límite:
Humans
Idioma:
En
Revista:
Toxicol Appl Pharmacol
Año:
2018
Tipo del documento:
Article
País de afiliación:
China