Abstract
Bruton’s tyrosine kinase (BTK) is a critical terminal enzyme in the B-cell antigen receptor (BCR) pathway. BTK activation has been implicated in the pathogenesis of certain B-cell malignancies. Targeting this pathway has emerged as a novel target in B-cell malignancies, of which ibrutinib is the first-in-class agent. A few other BTK inhibitors (BTKi) are also under development (e.g., acalabrutinib). While the predominant action of BTKi is the blockade of B-cell receptor pathway within malignant B-cells, increasing the knowledge of off-target effects as well as a potential role for B-cells in proliferation of solid malignancies is expanding the indication of BTKi into non-hematological malignancies. In addition to the expansion of the role of BTKi monotherapy, combination therapy strategies utilizing ibrutinib with established regimens and combination with modern immunotherapy compounds are being explored.
Highlights
Bruton’s Tyrosine Kinase (BTK) is a critical terminal kinase enzyme in the B-cell antigen receptor (BCR) signaling pathway
Epidermal growth factor receptor (EGFR) mutated non-small cell lung cancer (NSCLC) comprises approximately 15–20% of non-small cell lung cancer in white populations with higher rates in the order of 22–62% reported in Asian populations [19,20]
Studies of human epidermal growth factor receptor 2 (HER2) positive breast cancer cell lines have demonstrated ibrutinib causes reduction in phosphorylation of EGFR, HER2 and human epidermal growth factor receptor 3 (HER3) [30], effects that are off-target to its original purpose in Bruton’s tyrosine kinase (BTK) inhibition
Summary
Bruton’s Tyrosine Kinase (BTK) is a critical terminal kinase enzyme in the B-cell antigen receptor (BCR) signaling pathway. Ibrutinib efficacy is currently being explored in most B-cell malignancies including diffuse large B-cell lymphoma [11], follicular lymphoma [12], lymphoplasmacytic lymphoma [13], multiple myeloma [14], and primary CNS lymphoma [15] It has been studied in acute myeloid leukemia [16]. In addition to an expansion of the role of BTKi in non-B-cell malignancies, combination therapy strategies utilizing ibrutinib with established cytotoxic regimens as well as more modern immunotherapy compounds are being explored. This topic provides an update since the earlier paper by Berglof et al [18], and with a focus on the transition to clinical practice
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