B‐cell receptor signalling and its crosstalk with other pathways in normal and malignant cells

Abstract

The physiology of B cells is intimately connected with the function of their B-cell receptor (BCR). B-cell lymphomas frequently (dys)regulate BCR signalling and thus take advantage of this pre-existing pathway for B-cell proliferation and survival. This has recently been underscored by clinical trials demonstrating that small molecules (fosfamatinib, ibrutinib, idelalisib) inhibiting BCR-associated kinases (SYK, BTK, PI3K) have an encouraging clinical effect. Here we describe the current knowledge of the specific aspects of BCR signalling in diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, chronic lymphocytic leukaemia (CLL) and normal B cells. Multiple factors can contribute to BCR pathway (dys)regulation in these malignancies and the activation of 'chronic' or 'tonic' BCR signalling. In lymphoma B cells, the balance of initiation, amplitude and duration of BCR activation can be influenced by a specific immunoglobulin structure, the expression and mutations of adaptor molecules (like GAB1, BLNK, GRB2, CARD11), the activity of kinases (like LYN, SYK, PI3K) or phosphatases (like SHIP-1, SHP-1 and PTEN) and levels of microRNAs. We also discuss the crosstalk of BCR with other signalling pathways (NF-jB, adhesion through integrins, migration and chemokine signalling) to emphasise that the 'BCR inhibitors' target multiple pathways interconnected with BCR, which might explain some of their clinical activity.

Discovery of Pyrazolopyrimidine Derivatives as Novel Dual Inhibitors of BTK and PI3Kδ

“…To our satisfaction, 9−11 not only retained PI3Kδ activity but also gained activity against BTK, Table 1. In our assay, SW13 (2) demonstrated subnanomolar inhibition of PI3Kδ, which was in agreement with the value reported by Shokat, and no inhibition of BTK. Replacing the methylene-linked quinazolinone group of SW13 with a 2-indanyl in 9 increased BTK activity to 67 nM while maintaining single-digit nanomolar activity against PI3Kδ.…”

Ibrutinib inhibits CD20 upregulation on CLL B cells mediated by the CXCR4/SDF-1 axis

“…1,2 The small-molecule inhibitor of BTK kinase, ibrutinib, can disrupt CLL cells' capacity to interact with cells in the microenvironment by interfering with chemokine-receptor signaling, which is important for the chemotaxis of leukemia B cells to lymphoid tissues, and thus induce their massive and lasting mobilization in the peripheral blood. [1][2][3][4][5][6] The combined use of ibrutinib with anti-CD20 antibodies [7][8][9] or other monoclonal antibodies (mAbs) has been suggested for the treatment of patients with CLL because they use different mechanisms for antileukemia activity. Additionally, we and others have previously shown that microenvironmental interactions protect CLL and lymphoma cells from rituximab-induced cytotoxicity [10][11][12] and chemotherapyinduced apoptosis.…”

The Thermodynamic Overlapping pKa of the Antitumor Drug Ibrutinib Using Multiwavelength UV/VIS-Spectroscopy and Potentiometry

“…The most significant species (>10% in solution) were obtained for Ibrutinib. Once the solution pH increased, the following ionization sequence was obtained: LH 2 Figure 2, Ibrutinib is supposed to behave mostly as a neutral molecule LH 2 in biological relevant pH from 5 to 8. We also performed an ionic distribution analysis using Marvin and the obtained data were similar to the ones obtained with ACD/ percepta.…”

“…Ibrutinib (USAN, also known as PCI-32765 and marketed under the name Imbruvica) (Figure 1 Ibrutinib is currently under development by Pharmacyclics, Inc and Johnson & Johnson's Janssen Pharmaceutical division for additional B-cell malignancies including diffuse large B-cell lymphoma and multiple myeloma [1,2]. In January 2015, Ibrutinib was approved by the FDA for treatment of Waldenström's macroglobulinemia, a form of non-Hogkin´s lymphoma.…”

“…In January 2015, Ibrutinib was approved by the FDA for treatment of Waldenström's macroglobulinemia, a form of non-Hogkin´s lymphoma. lymphocytic leukemia (CLL) cells, Ibrutinib has been reported to promote apoptosis, inhibit proliferation, and also prevent CLL cells from responding to survival stimuli provided by the microenvironment [1,2]. In early clinical studies, the activity of Ibrutinib has been described to include a rapid reduction in lymphadenopathy accompanied by transient lymphocytosis, suggesting that the drug might have direct effects on cell homing or migration to factors in tissue microenvironments [3].…”