Targeting the B cell receptor pathway in non-Hodgkin lymphoma

Abstract

Introduction: Dysregulated B cell receptor (BCR) signaling has been identified as a potent contributor to tumor survival in B cell non-Hodgkin lymphomas (NHLs). This pathway's emergence as a rational therapeutic target in NHL led to development of BCR-directed agents, including inhibitors of Bruton's tyrosine kinase (BTK), spleen tyrosine kinase (SYK), and phosphatidylinositol 3 kinase (PI3K). Several drugs have become valuable assets in the anti-lymphoma armamentarium.

Areas covered: We provide an overview of the BCR pathway, its dysregulation in B cell NHL, and the drugs developed to target BCR signaling in lymphoma. Mechanisms, pharmacokinetics, pharmacodynamics, efficacy, and toxicity of currently available BTK, SYK, and PI3K inhibitors are described.

Expert opinion: While the excellent response rates and favorable toxicity profile of the BTK inhibitor ibrutinib in certain NHL subtypes have propelled it to consideration as frontline therapy in selected populations, additional data and clinical studies are needed before other agents targeting BCR signaling influence clinical practice similarly. PI3K inhibitors remain an option for some relapsed indolent lymphomas and chronic lymphocytic leukemia, but their widespread use may be limited by adverse effects. Future research should include efforts to overcome resistance to BTK inhibitors, combination therapy using BCR-targeted agents, and exploration of novel agents.

Keywords: B cell receptor; fostamatinib; ibrutinib; non-Hodgkin lymphoma.

Figure 1.. B cell receptor (BCR) signaling pathways.

BCR may be activated either by antigen binding or via cell-autonomous pathways. Antigen binding to extracellular BCR results in phosphorylation of immunoreceptor tyrosine-based activation motifs (ITAMs) within CD79a and CD79b, which act as intracellular docking sites for additional adaptor molecules and kinases such as LYN. LYN phosphorylates the tyrosine kinase SYK to continue signal propagation. SYK is also activated through autophosphorylation when bound directly to phosphorylated ITAMs, at which point it promotes further ITAM phosphorylation and activates downstream signaling cascades, including those mediated by Bruton’s tyrosine kinase (BTK) and phosphatidylinositol 3 kinase (PI3K). PI3K activation generates PIP3, which complexes with AXL and BLNK to recruit BTK, PLCγ2, and AKT to the plasma membrane. Tonic BCR activity is mediated by the PI3K/AKT pathway, which coordinates downstream pro-survival effectors and cell cycle regulators. In a separate pathway, activation of PLCγ2 downstream of BTK activates PKCβ, which phosphorylates IKK recruited by a complex of MALT1, BCL10, and CARD11. Phosphorylated IKK activates NF-κB transcription factors that translocate to the nucleus to promote expression of genes associated with survival and proliferation. A20 acts as a negative regulator of NF- κB, while SHIP-1 and PTEN phosphatases inhibit PI3K signaling by hydrolyzing PIP3.