Targeting B cell receptor signalling in cancer: preclinical and clinical advances

Key Points B cell receptor (BCR) signalling is indispensable for normal B cell development and adaptive immunity. In some B cell leukaemias and lymphomas, malignant B cells utilize BCR signalling for growth and survival. The mechanism of activation of BCR signalling includes continuous BCR stimulation by microbial antigens and/or autoantigens that are present in the tissue microenvironment, oncogenic mutations within the BCR complex or downstream signalling components and ligand-independent tonic BCR signalling. Bruton tyrosine kinase (BTK) inhibitors and/or PI3Kδ selective inhibitors are effective against chronic lymphocytic leukaemia (CLL), mantle cell lymphoma, follicular lymphoma, Waldenstrom macroglobulinaemia (WM) and other selective B cell malignancies. In CLL and WM, BTK inhibitors are increasingly replacing chemotherapy. BTK and PI3Kδ inhibitors cause redistribution of malignant B cells from tissue sites into the peripheral blood, especially in patients with CLL. How much this redistribution, resulting in a form of programmed cell death (anoikis) as a consequence of detachment of the malignant cells from their supportive tissue microenvironment, contributes to the efficacy of these agents remains unclear. The involvement of BTK, PI3Kδ and other BCR-related kinases such as spleen tyrosine kinase (SYK) in the signalling and function of homing receptors (chemokine receptors and integrins) appears to be the molecular basis for this B cell redistribution. BTK and PI3Kδ are also expressed in non-malignant cells in the microenvironment, such as T cells and monocytes and macrophages. The effects of BTK and PI3Kδ inhibitors extend to these cell lineages, which may contribute to antitumour effects but can give rise to side effects. In addition, ibrutinib, the most widely used BTK inhibitor, also targets inducible T cell kinase (ITK), a related kinase that promotes T helper 2 (T H 2) cell differentiation. B cells and macrophages are part of a tumour-supportive microenvironment in solid tumours, including pancreatic cancer. Targeting B cell and/or macrophage function yields antitumour effects in preclinical models, and this strategy is being investigated in ongoing clinical trials. In this Review, Burger and Wiestner describe the latest insights into B cell receptor (BCR) signalling with respect to its contribution to B cell malignancies and discuss how inhibitors that target kinases downstream of the BCR are changing treatment outcomes for patients with B ce