Rabbit Anti-Human Btk (phospho Tyr223) (a.a. 188-237) Polyclonal antibody

Purpose of Review Recent advances the genomic profiling of patients with Waldenstrom macroglobulinemia (WM) have led to the identification of novel therapeutic targets in these patients. In this review, we cover the current standard of care and the recently evaluated novel approaches with high potential to be incorporated in the therapeutic armamentarium against WM. Recent Findings The MYD88(L265P) mutation is the most common genomic abnormality in WM, and is encountered in 80-95% of patients, making it an important target for drug development. The success of the first-generation Bruton tyrosine kinase (BTK) inhibitor, ibrutinib, has generated tremendous interest in the study of more selective and potent BTK inhibitors. Additionally, the identification of CXCR4(WHIM) mutations in up to approximately 40% of patients with WM has fueled research regarding their implication on systemic therapy in WM. In a rapidly advancing field of targeted therapies, the treatment options for patients with WM are expanding as researchers continue to uncover and harness the survival pathways active in this hematologic malignancy.

Apoptosis-regulating BCL-2 family members, which can promote malignant transformation and resistance to therapy, have become prime therapeutic targets, as illustrated by the striking efficacy in certain lymphoid malignancies of the BCL-2-specific inhibitor venetoclax. In other lymphoid malignancies, however, such as the aggressive mantle cell lymphoma (MCL), cell survival might rely instead or also on BCL-2 relative MCL-1. We have explored MCL-1 as a target for killing MCL cells by both genetic and pharmacologic approaches. In several MCL cell lines, MCL-1 knockout with an inducible CRISPR/Cas9 system triggered spontaneous apoptosis. Accordingly, most MCL cell lines proved sensitive to the specific MCL-1 inhibitor S63845, and MCL-1 inhibition also proved efficacious in an MCL xenograft model. Furthermore, its killing efficacy rose on combination with venetoclax, the BCL-X-L-specific inhibitor A-1331852, or Bruton's tyrosine kinase (BTK) inhibitor ibrutinib, which reduced pro-survival signals. We also tested the MCL-1 inhibitor in primary samples from 13 MCL patients, using CD40L-expressing feeder cells to model their microenvironmental support. Notably, all unstimulated primary MCL samples were very sensitive to S63845, but the CD40L stimulation attenuated their sensitivity. Mass cytometric analysis revealed that the stimulation likely conveyed protection by elevating BCL-X-L and MCL-1. Accordingly, sensitivity of the CD40L-stimulated cells to S63845 was substantially restored by co-treatment with venetoclax, the BCL-X-L-specific inhibitor or ibrutinib. Overall, our findings indicate that MCL-1 is very important for survival of MCL cells and that the MCL-1 inhibitor, both alone and together with ibrutinib, venetoclax or a BCL-X-L inhibitor, offers promise for novel improved MCL therapies.