acp-196 and Carcinogenesis

Neuroblastoma, a common childhood tumor, remains one of the most elusive diseases to treat. To date, high-risk neuroblastoma is associated with low survival rates. To address this, novel and more effective therapeutic strategies must continue to be explored.. We employed a bioinformatics approach corroborated with in vitro and in vivo data. Samples from neuroblastoma patients were retrieved and immuno-stained for Bruton's tyrosine kinase (BTK). To evaluate its effect on cellular functions, BTK expression in SK-N-BE(2) and SH-SY5Y neuroblastoma cells was downregulated using gene silencing or inhibition with ibrutinib or acalabrutinib. Xenograft mouse models were used to investigate the in vivo role of BTK in neuroblastoma tumorigenesis.. We found that BTK was highly expressed in primary neuroblastoma samples, preferentially in MYCN-amplified neuroblastoma cases, and was associated with a poor prognosis. Immunohistochemical staining of tissues from our neuroblastoma cohort revealed a strong BTK immunoreactivity. We also found that neuroblastoma SK-N-BE(2) and SH-SY5Y cells were sensitive to treatment with ibrutinib and acalabrutinib. Pharmacologic or molecular inhibition of BTK elicited a reduction in the migratory and invasive abilities of neuroblastoma cells, and ibrutinib considerably attenuated the neurosphere-forming ability of neuroblastoma cells. Both inhibitors showed synergism with cisplatin. In vivo assays showed that acalabrutinib effectively inhibited neuroblastoma tumorigenesis.. From our data we conclude that BTK is a therapeutically targetable driver of neuroblastoma.

Topics: Agammaglobulinaemia Tyrosine Kinase; Animals; Antineoplastic Agents; Benzamides; Carcinogenesis; Caspase 3; Cell Line, Tumor; Cell Movement; Cisplatin; Female; Gene Expression Regulation, Neoplastic; Humans; Ki-67 Antigen; Male; Mice, Inbred NOD; Mice, SCID; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplastic Stem Cells; Neuroblastoma; Phenotype; Prognosis; Proto-Oncogene Proteins c-akt; Pyrazines; Spheroids, Cellular; STAT3 Transcription Factor