Bruton's tyrosine kinase (BTK) as a promising target in solid tumors. (July 2017)

• Record Type: Journal Article
• Authors: Molina-Cerrillo, J.; Alonso-Gordoa, T.; Gajate, P.; Grande, E.
• Is Part Of: Cancer treatment reviews. Volume 58(2017)
• Page Start: 41
• Page End: 50
• Publication Date: 2017-07
• Subjects: Ibrutinib -- Bruton tirosine kinase -- Solid tumors -- Checkpoint inhibitors -- Tumor microenvironment -- TEC kinases; Cancer -- Periodicals; Cancer -- Treatment -- Periodicals; Neoplasms -- therapy -- Periodicals; Cancer -- Périodiques; Cancer -- Traitement -- Périodiques; Cancer -- Treatment; Electronic journals; Periodicals; 616.99406
• DOI: 10.1016/j.ctrv.2017.06.001
• Languages: English
• ISSNs: 0305-7372

Abstract

Highlights: BTK is a TEC-family kinases member, expressed in lymphocytes and other cell subtypes. TEC kinases inhibition by Ibrutinib has promising results in cancer cellular models. Ibrutinib is able to modify the tumor microenvironment with therapeutic implications. BTK inhibitors may have synergistic effect with other active drugs in solid tumors. Abstract: Bruton's tyrosine kinase (BTK) is a non-receptor intracellular kinase that belongs to the TEC-family tyrosine kinases together with bone marrow-expressed kinase (BMX), redundant-resting lymphocyte kinase (RLK), and IL-2 inducible T-Cell kinase (ITK). All these proteins play a key role in the intracellular signaling of both B and T lymphocytes. Recently, some preclinical data have demonstrated that BTK is present in certain tumor subtypes and in other relevant cells that are contributing to the tumor microenvironment such as dendritic cells, macrophages, myeloid derived suppressor cells and endothelial cells. Ibrutinib (PCI-32765) is an orally available small molecule that acts as an inhibitor of the BTK and is approved for the treatment of patients with some hematological malignancies. It has been suggested that ibrutinib may also have a potential antitumor activity in solid neoplasms. In this sense, ibrutinib has the ability to revert polarization of TCD4+ to Th1 lymphocytes to increase the cytotoxic ability of T CD8+ and to regulate tumor-induced immune tolerance by acting over tumor infiltrating cells activity and immunosuppressive cytokines release. Furthermore, based on its molecular activity and safety, ibrutinib has been considered as a partner for treatment combination with PI3K/AKT/mTOR inhibitors or with immune-checkpoint inhibitors, inhibiting immunosuppressive signals from the tumor microenvironment, and overcoming the immune resistance to current anti-PD1/PDL1 immunotherapeutic drugs by the CXCR4/CXCL2 pathway regulation. Currently, a broad range of different studies are evaluating the activity of ibrutinib either as single agent or in combination in patients with solid tumors.