<b>Purpose:</b> Ibrutinib, a Bruton tyrosine kinase (BTK) inhibitor, is approved for the treatment of relapsed chronic lymphocytic leukemia (CLL) and CLL with del17p.
<i>In vitro</i> studies support the effectiveness of combing PI3Kδ and BTK inhibitors.<b>Experimental Design:</b> As CLL proliferation and survival depends on the microenvironment, we used murine models to assess the efficacy of the BTK inhibitor acalabrutinib combined with the PI3Kδ inhibitor ACP-319 <i>in vivo</i> We compared single-agent with combination therapy in TCL1-192 cell-injected mice, a model of aggressive CLL.<b>Results:</b> We found significantly larger reductions in tumor burden in the peripheral blood and spleen of combination-treated mice.
Bruton's tyrosine kinase (BTK) regulates the B-cell receptor (BCR) signaling pathway, which, in turn, plays a critical role in B-cell chronic lymphocytic leukemia (B-CLL) pathogenesis.
A head-to-head comparison of ibrutinib and acalabrutinib in CLL cell cultures and healthy T cells is needed to understand preclinical biologic and molecular effects.<b>Experimental Design:</b> Using samples from patients with CLL, we compared the effects of both BTK inhibitors on biologic activity, chemokine production, cell migration, BTK phosphorylation, and downstream signaling in primary CLL lymphocytes and on normal T-cell signaling to determine the effects on other kinases.<b>Results:</b> Both BTK inhibitors induced modest cell death accompanied by cleavage of PARP and caspase-3.
A major revolution in the treatment of chronic lymphocytic leukemia (CLL) began with the approval of ibrutinib, a first-in-class oral inhibitor of Bruton tyrosine kinase (BTK), for the treatment of relapsed/refractory (R/R) and/or TP53 mutated patients with CLL.
A number of new treatment options have recently emerged for chronic lymphocytic leukemia (CLL) patients, including the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib, phosphatidylinositol-3-kinase (PI3K) delta isoform inhibitor idelalisib combined with rituximab, the Bcl-2 antagonist venetoclax, and the new anti-CD20 antibodies obinutuzumab and ofatumumab.
Acalabrutinib, a highly selective Bruton's tyrosine kinase inhibitor, is associated with high overall response rates and durable remission in previously treated chronic lymphocytic leukemia (CLL); however, complete remissions were limited.
Acalabrutinib, a more specific BTK inhibitor now in development, also appears to be highly effective in CLL, but the connection of its mechanism with CLL cell death is also unclear.
Agents targeting B-cell receptor (BCR) signaling-associated kinases such as Bruton tyrosine kinase (BTK) or phosphatidylinositol 3-kinase can induce mobilization of neoplastic B cells from the lymphoid tissues into the blood, which makes them potentially ideal to combine with anti-CD20 monoclonal antibodies (such as rituximab, obinutuzumab, or ofatumumab) for treatment of B-cell lymphomas and chronic lymphocytic leukemia (CLL).
Although rituximab-based immunochemotherapy remains the standard of treatment for chronic lymphocytic leukemia (CLL), the importance of Bruton's tyrosine kinase inhibitors such as ibrutinib is steadily increasing.
Areas covered: This review highlights key aspects of BTK, PI3K and BCL-2 inhibitors that are currently at various stages of preclinical and clinical development in CLL.
Areas covered: Unique properties of both CLL and ibrutinib that complicate attempts to definitively conclude whether BTK/PLCG2 mutations are passengers or drivers of ibrutinib-resistant disease are reviewed.
As just reported by previous report, Richter syndrome developing after ibrutinib therapy lacked resistance mutations of the BTK and PLCG2 genes, which are clonally related to the pre-existent CLL phase representing transformation from CLL.
Based on our previous finding that a humanized monoclonal antibody against ROR1 increases the activity of Ibrutinib against CLL, which is currently undergoing evaluation in clinical trials for the treatment of B-cell lymphoid malignancies, we then provided evidence that treatment with HSP90i (17-DMAG) enhances anti-CLL activity of Ibrutinib in vitro and in vivo, by down-modulating ROR1. iTRAQ-based quantitative proteomic analysis of other HSP90 oncogenic clients in addition to ROR1, followed by GO/KEGG enrichment analysis, showed that Bruton's Tyrosine Kinase (BTK), B-lymphoid Tyrosine Kinase (BLK), Lymphocyte-specific Protein Tyrosine Kinase (LCK), or LCK/YES-Related Novel Protein Tyrosine Kinase (LYN), as HSP90 clients, were significantly involved in 11 biological processes and 6 signaling pathways.
BRAF inhibitor-driven ERK activity and CLL proliferation required B cell antigen receptor (BCR) activation, as inhibition of the BCR-proximal spleen tyrosine kinase (SYK) reversed ERK hyperactivation and proliferation of CLL cells from multiple patients, while inhibition of the BCR-distal Bruton tyrosine kinase had no effect.
Chronic activation of the Bruton's tyrosine kinase (BTK)-mediated B-cell receptor (BCR) signaling is a hallmark of many B-cell lymphoid malignancies, including chronic lymphocytic leukemia (CLL) and diffuse large B-cell lymphoma (DLBCL).
Current targeted agents in CLL are directed against B cell receptor-associated tyrosine kinases such as BTK and SYK, the downstream PI3-kinase pathway, as well as the antiapoptotic protein BCL-2.
Currently, inhibitors of kinases like BTK or PI3K blocking BCR signaling, and molecules that mimic the BH3 domain to compete with BCL-2 are established tools in the treatment of CLL.
Currently, the Bruton tyrosine kinase (BTK) inhibitor ibrutinib, which acts downstream the BCR signaling pathway, appears to be particularly promising and shows important clinical activity in CLL.