Effects of ibrutinib on proliferation and histamine release in canine neoplastic mast cells

Abstract

The Bruton's tyrosine kinase (BTK) inhibitor ibrutinib is effective in the treatment of human chronic lymphocytic leukaemia and mantle cell lymphoma. Recent data have shown that ibrutinib also blocks IgE‐dependent activation and histamine release in human basophils (BAs) and mast cells (MCs). The aim of this study was to investigate whether BTK serves as a novel therapeutic target in canine mast cell tumours (MCTs). We evaluated the effects of ibrutinib on two canine MC lines, C2 and NI‐1 and on primary MCs obtained from canine MCTs (n = 3). Using flow cytometry, we found that ibrutinib suppresses phosphorylation of BTK and of downstream STAT5 in both MC lines. In addition, ibrutinib decreased proliferation of neoplastic MCs, with IC50 values ranging between 0.1 and 1 μM in primary MCT cells and between 1 and 3 μM in C2 and NI‐1 cells. In C2 cells, the combination “ibrutinib + midostaurin” produced synergistic growth‐inhibitory effects. At higher concentrations, ibrutinib also induced apoptosis in both MC lines. Finally, ibrutinib was found to suppress IgE‐dependent histamine release in primary MCT cells, with IC50 values ranging from 0.05 to 0.1 μM in NI‐1 cells, and from 0.05 to 1 μM in primary MCT cells. In summary, ibrutinib exerts anti‐proliferative effects in canine neoplastic MCs and counteracts IgE‐dependent histamine release in these cells. Based on our data, ibrutinib may be considered as a novel therapeutic agent for the treatment of canine MCT. The value of BTK inhibition in canine MCT patients remains to be elucidated in clinical trials.

The Use of Bruton’s Tyrosine Kinase Inhibitors to Treat Allergic Disorders

“…At this time, there is no evidence to suggest that BTKis deplete mast cells or otherwise stunt their maturation. Prior studies found that ibrutinib can reduce the survival and proliferation of canine mast cell lines and canine neoplastic mast cells [ 53 ]; however, our own (unpublished) data found no differences in proliferation or survival of human skin-derived mast cells after treatment with ibrutinib, tirabrutinib, or acalabrutinib. In vivo data in food allergic adults and humanized mice demonstrate reversibility of BTKis’ effects after short courses (up to seven days of treatment) [ 9 ••, 21 ••], suggesting that, at least during short-term use, BTKis are unlikely to affect mast cell survival in vivo.…”

Bruton’s tyrosine kinase inhibition effectively protects against human IgE-mediated anaphylaxis

“…We and others have previously shown that in vitro pretreatment of human basophils with the first-generation BTKi ibrutinib or the second-generation BTKi acalabrutinib abolishes their IgE-mediated activation (6,(12)(13)(14), and that 2 FDA-approved doses of ibrutinib prevents IgE-mediated basophil activation ex vivo (11). Prior studies have also demonstrated ibrutinib's ability to inhibit IgE-mediated degranulation in canine neoplastic mast cells (15). We therefore sought to investigate the effects of BTKis on IgE-mediated activation of human mast cells.…”

BTK and PI3K Inhibitors Reveal Synergistic Inhibitory Anti-Tumoral Effects in Canine Diffuse Large B-Cell Lymphoma Cells

“…Among them, BTK and PI3K inhibitors have exhibited encouraging clinical results. On the one hand, the BTK inhibitor ibrutinib has significant value for the treatment of human DLBCL patients, particularly with ABC-DLBCL subtype [ 7 ], and has been shown to exert dose-dependent proliferation inhibition and IgE-dependent histamine release suppression in a pre-clinical model of canine mast cell tumor [ 21 ]. Further, although ibrutinib has not yet been approved for veterinary medicine, a dose-escalation study has been performed in dogs [ 22 ].…”