Targets for Ibrutinib Beyond B Cell Malignancies

Abstract

Ibrutinib (Imbruvica™) is an irreversible, potent inhibitor of Bruton's tyrosine kinase (BTK). Over the last few years, ibrutinib has developed from a promising drug candidate to being approved by FDA for the treatment of three B cell malignancies, a truly remarkable feat. Few, if any medicines are monospecific and ibrutinib is no exception; already during ibrutinib's initial characterization, it was found that it could bind also to other kinases. In this review, we discuss the implications of such interactions, which go beyond the selective effect on BTK in B cell malignancies. In certain cases, the outcome of ibrutinib treatment likely results from the combined inhibition of BTK and other kinases, causing additive or synergistic, effects. Conversely, there are also examples when the clinical outcome seems unrelated to inhibition of BTK. Thus, more specifically, adverse effects such as enhanced bleeding or arrhythmias could potentially be explained by different interactions. We also predict that during long‐term treatment bone homoeostasis might be affected due to the inhibition of osteoclasts. Moreover, the binding of ibrutinib to molecular targets other than BTK or effects on cells other than B cell‐derived malignancies could be beneficial and result in new indications for clinical applications.

Response of renal cell carcinoma to ibrutinib, a bruton tyrosine kinase inhibitor, in a patient treated for chronic lymphocytic leukemia

“…[7][8][9] This mechanism is believed to potentiate immunomodulatory effects of checkpoint inhibitors nivolumab and ipilimumab (inhibitor of cytotoxic T-lymphocyte-associated protein, CTLA-4). 3,7 Checkpoint inhibitors are an emerging therapeutic modality for metastatic RCC. 10,11 In a phase 3 clinical trial …”

“…2 Only a small subset of tyrosine kinases in the human genome is predicted to contain a modifiable cysteine residue homologous to cysteine 481 in BTK. 1,3 These include EGFR, HER2, HER4, ITK, BMX, JAK3, TEC, and BLK. 1,3 To what extent inhibition of these kinases contributes to efficacy of ibrutinib is unknown.…”

“…1,3 These include EGFR, HER2, HER4, ITK, BMX, JAK3, TEC, and BLK. 1,3 To what extent inhibition of these kinases contributes to efficacy of ibrutinib is unknown. Ibrutinib was approved by the Federal Drug Agency for treatment of B cell malignancies including CLL, mantle cell lymphoma, multiple myeloma, diffuse large B cell lymphoma, and Waldenstrӧm's macroglobulinemia between 2013 and 2015.…”

Pharmacokinetic and pharmacodynamic evaluation of ibrutinib for the treatment of chronic lymphocytic leukemia: rationale for lower doses

“…Some off-target effects of ibrutinib have been recognized for their potential therapeutic benefit in other diseases, e.g., inhibition of ITK and resultant Th1 “skewing” in Th2-mediated diseases like asthma, inhibition of BTK and TEC in overactive osteoclasts in osteoporosis and rheumatoid arthritis, and inhibition of BTK, ITK and TEC in mast cells in allergic conditions and pancreatic tumors. [37]…”

“…[37] Other kinases targeted by ibrutinib include the HER family kinases EGFR, HER2/ErbB2 and HER4/ErbB4, and JAK3 (Table 1). [37, 46] Ibrutinib inhibits yet other kinases at low nanomolar concentrations, e.g., BRK, CSK, FRG, HCK, BLK; indeed, the IC 50 for BLK is the same as for BTK, i.e., 0.5 nM.…”