NT157, an IGF1R-IRS1/2 inhibitor, exhibits antineoplastic effects in pre-clinical models of chronic myeloid leukemia.
Invest New Drugs
; 39(3): 736-746, 2021 06.
Article
em En
| MEDLINE
| ID: mdl-33403501
ABSTRACT
Chronic myeloid leukemia (CML) is successfully treated with BCR-ABL1 tyrosine kinase inhibitors, but a significant percentage of patients develop resistance. Insulin receptor substrate 1 (IRS1) has been shown to constitutively associate with BCR-ABL1, and IRS1-specific silencing leads to antineoplastic effects in CML cell lines. Here, we characterized the efficacy of NT157, a pharmacological inhibitor of IGF1R-IRS1/2, in CML cells and observed significantly reduced cell viability and proliferation, accompanied by induction of apoptosis. In human K562 cells and in murine Ba/F3 cells, engineered to express either wild-type BCR-ABL1 or the imatinib-resistant BCR-ABL1T315I mutant, NT157 inhibited BCR-ABL1, IGF1R, IRS1/2, PI3K/AKT/mTOR, and STAT3/5 signaling, increased CDKN1A, FOS and JUN tumor suppressor gene expression, and reduced MYC and BCL2 oncogenes. NT157 significantly reduced colony formation of human primary CML cells with minimal effect on normal hematopoietic cells. Exposure of primary CML cells harboring BCR-ABL1T315I to NT157 resulted in increased apoptosis, reduced cell proliferation and decreased phospho-CRKL levels. In conclusion, NT157 has antineoplastic effects on BCR-ABL1 leukemogenesis, independent of T315I mutational status.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Contexto em Saúde:
6_ODS3_enfermedades_notrasmisibles
Base de dados:
MEDLINE
Assunto principal:
Pirogalol
/
Sulfonamidas
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Leucemia Mielogênica Crônica BCR-ABL Positiva
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Receptor IGF Tipo 1
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Inibidores de Proteínas Quinases
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Proteínas Substratos do Receptor de Insulina
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Antineoplásicos
Tipo de estudo:
Prognostic_studies
Limite:
Animals
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Humans
Idioma:
En
Revista:
Invest New Drugs
Ano de publicação:
2021
Tipo de documento:
Article