New players in the Bruton’s tyrosine kinase vs. ibrutinib match

The Bruton’s tyrosine kinase, also known as BTK, is a member of the Tec family kinases with a well-characterized role in B-cell receptor (BCR) signaling and B-cell activation. BTK is able to transmit and amplify several signals that are involved in the complex crosstalk between tumor cells and microenvironment. These signals include cytokines and growth factors, chemokine receptors, antigen receptors as BCR and integrins (1). Chronic lymphocytic leukemia (CLL) cells show an increased expression and activation of BTK that with a chain reaction modulates signaling pathways essential for CLL-cells survival, as the protein kinase AKT, extracellular signal-regulated kinase (ERK) and nuclear factor kappa light-chain enhancer of activated B cells (NF-κB) pathways (2). In addition, BTK is involved in chemokine-mediated migration, homing and adhesion of CLL cells (3). Given the known importance of BCR signaling in CLL and the central role of BTK in this pathway, in the recent years a new drug called ibrutinib has been used in clinical practice to induce inhibition of this kinase. Ibrutinib is a relatively selective, irreversible inhibitor of BTK binding covalently the Cys-481 in the ATP binding domain of the kinase. Inhibition of BTK in CLL cells leads to an impressive delocalization of leukemic cells from the protective tissue microenvironment to the periphery interfering with pathogenic mechanism of recirculation and homing. Several studies demonstrate the considerable clinical success of ibrutinib showing a good safety profile determining an improvement of the quality of life of CLL patients (4).