The ALK inhibitors, alectinib and ceritinib, induce ALK-independent and STAT3-dependent glioblastoma cell death.
Cancer Sci
; 112(6): 2442-2453, 2021 Jun.
Article
em En
| MEDLINE
| ID: mdl-33728771
ABSTRACT
Glioblastoma (GBM) is the most common, but extremely malignant, brain tumor; thus, the development of novel therapeutic strategies for GBMs is imperative. Many tyrosine kinase inhibitors (TKIs) have been approved for various cancers, yet none has demonstrated clinical benefit against GBM. Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase (RTK) that is confirmed only during the embryonic development period in humans. In addition, various ALK gene alterations are known to act as powerful oncogenes and therapeutic targets in various tumors. The antitumor activity of various TKIs was tested against three human GBM cell lines (U87MG, LN229, and GSC23), which expressed substantially low ALK levels; second-generation ALK inhibitors, alectinib and ceritinib, effectively induced GBM cell death. In addition, treatment with either alectinib or ceritinib modulated the activation of various molecules downstream of RTK signaling and induced caspase-dependent/-independent cell death mainly by inhibiting signal transducer and activator of transcription 3 activation in human GBM cells. In addition, alectinib and ceritinib also showed antitumor activity against a U87MG cell line with acquired temozolomide resistance. Finally, oral administration of alectinib and ceritinib prolonged the survival of mice harboring intracerebral GBM xenografts compared with controls. These results suggested that treatment with the second-generation ALK inhibitors, alectinib and ceritinib, might serve as a potent therapeutic strategy against GBM.
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Base de dados:
MEDLINE
Assunto principal:
Piperidinas
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Pirimidinas
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Sulfonas
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Neoplasias Encefálicas
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Carbazóis
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Glioblastoma
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Fator de Transcrição STAT3
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Quinase do Linfoma Anaplásico
Idioma:
En
Ano de publicação:
2021
Tipo de documento:
Article