Bruton's tyrosine kinase inhibitors in B‐cell non‐Hodgkin's lymphomas

Abstract

The B-cell receptor pathway (BCR) is aberrantly activated in select B-cell malignancies. This knowledge has allowed for the development of inhibitors of different crucial steps of this pathway. Bruton's tyrosine kinase (BTK) is a key component of BCR signaling and functions as an important regulator of multiple cell functions including differentiation, proliferation, and survival in various B-cell malignancies. Ibrutinib is a potent, selective BTK inhibitor that has shown significant activity in specific subtypes of B-cell non-Hodgkin's lymphomas (NHLs). Given the high response rates, tolerability, and acceptable toxicities, ibrutinib was recently approved by the US Food and Drug Administration (FDA) for the treatment of patients with relapsed mantle cell lymphoma and chronic lymphocytic leukemia. It is also currently being evaluated in combination with chemotherapy and as frontline therapy in B-cell NHL. This review summarizes the preclinical and clinical development of ibrutinib in the treatment of B-cell NHL.

Preclinical investigation of ibrutinib, a Bruton's kinase tyrosine (Btk) inhibitor, in suppressing glioma tumorigenesis and stem cell phenotypes

“…First, a significantly higher Btk expression is detected in clinical glioma samples from different public databases where Btk expression is generally low in most tissues except for the hematopoietic lineages and organs such as lung and spleen. High Btk expression is well established in B-cell malignancies such as chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL); inhibition of Btk-signaling pharmacologically by FDA-approved Btk inhibitor, ibrutinib, has been shown to be effective in managing these diseases [7, 15]. According to our database analyses, Btk mRNA level is several fold higher in astrocytoma, glioblastoma and secondary glioblastoma clinical samples as compared to the normal astrocytes.…”

“…Ibrutinib (Ib) is a FDA-approved Btk inhibitor for treating chronic lymphocytic leukemia [7]. Here, we intended to examine whether Ib treatment via a pharmacological means of down-regulating Btk, in GBM cells would yield similar anti-GBM activities as observed in Btk-silenced cells.…”

“…Btk regulates key signaling pathways such as PI3K, PLCγ and PKC which suggest their involvements in cellular growth, differentiation and apoptosis. Recently, a new role of this family of kinases is emerging in regulating cytoskeletal reorganization and cell motility [5, 7]. Previously, Btk dysregulation has been mainly attributed to the development of B-cell malignancy.…”

The preclinical discovery of rituximab for the treatment of non-Hodgkin’s lymphoma

“…These antibodies can create an alternative or complementary strategy to circumvent resistance to, or the failure of, anti-CD20 MoAb therapies associated with low levels of CD20 expression. In addition, the inhibitors of the BCR pathway, the BTK signaling pathway inhibitor, ibrutinib, and the selective inhibitor of PI3K, idelalisib, might soon become key treatments for NHL due to their high potency and favorable toxicity profile [162,163]. These drugs are available in oral preparations and are given as continuous treatment.…”

B-cell receptor pathway modulators in NHL

“…Clin Pharmacol Ther 2015 39 ). B-Cell Receptor (BCR) signaling is a critical component of B cell activation, proliferation, survival, and migration in normal as well as malignant B cells.…”