High expression of Bruton’s tyrosine kinase (BTK) is required for EGFR-induced NF-κB activation and predicts poor prognosis in human glioma

Abstract

BackgroundMalignant glioma is the most common primary brain tumor in adults and has a poor prognosis. However, there are no effective targeted therapies for glioma patients. Thus, the development of novel targeted therapeutics for glioma is urgently needed.MethodsIn this study, we examined the prognostic significance BTK expression in patients with glioma. Furthermore, we investigated the mechanism and therapeutic potential of ibrutinib in the treatment of human glioma in vitro and in vivo.ResultsOur data demonstrate that high expression of BTK is a novel prognostic marker for poor survival in patients with glioma. BTK-specific inhibitor ibrutinib effectively inhibits the proliferation, migration and invasion ability of glioma cells. Furthermore, ibrutinib can induce G1 cell-cycle arrest by regulating multiple cell cycle-associated proteins. More importantly, we found that BTK inhibition significantly blocks the degradation of IκBα and prevents the nuclear accumulation of NF-κB p65 subunit induced by EGF in glioma cells.ConclusionsTaken together, our study suggests that BTK is a novel prognostic marker and molecular therapeutic target for glioma. BTK is required for EGFR-induced NF-κB activation in glioma cells. These findings provide the basis for future clinical studies of ibrutinib for the treatment of glioma.

PHAP1 promotes glioma cell proliferation by regulating the Akt/p27/stathmin pathway

“…Depression of specific tumour suppressor genes or activation of specific oncogenes is a key event for the development and malignant progression of glioblastoma. [32][33][34] Particularly, the molecules modulating the expression of PI3K/Akt pathway are important for the survival of cancer cells. 35 Akt has been regarded as a very valuable therapeutic target in glioma due to the alteration of multiple signalling pathways in glioma that converge to Akt, as well as, the aggressive characteristics of glioma that regulate genes involved in cell proliferation, apoptosis, migration, invasion and neoangiogenesis.…”

Novel Indications for Bruton’s Tyrosine Kinase Inhibitors, beyond Hematological Malignancies

“…Chemoradiotherapy is central to the management of this disease, however, prognosis remains poor, with limited cytotoxic choices due to the necessity of blood-brain barrier penetration of any therapeutic. The prognostic significance of BTK expression in glioma has been studied, with high expression of BTK proposed as a novel prognostic marker [ 48 ]. Bioinformatics data indicate that BTK is significantly higher in clinical glioma samples compared to normal brain cells, with higher levels of BTK mRNA described in GBM compared with normal brain and astrocyte samples [ 49 ].…”

Decreased NOTCH1 Activation Correlates with Response to Ibrutinib in Chronic Lymphocytic Leukemia

“…In many tumor subtypes, ibrutinib appears to work via several intracellular signals of cancer growth demonstrating that this drug is not entirely specific in its binding to BTK (39,40). Ibrutinib efficacy was associated to a direct anti-EGFR effect in lung cancer (41) or to the activity against EGFR-induced NF-kB activation in glioma (42). In addition, ibrutinib reduced phosphorylated HER2 and AKT in breast cancer (43), while sensitivity to inhibition of BTK has been demonstrated in MYC-amplified esophageal tumor lines (44).…”