BCR Signaling & Therapeutic Targeting
The prominent role of the BCR signaling in promoting B-CLL cell survival has prompted new therapeutic strategies targeted to signalosome elements. In particular, the most advanced BCR-signaling targets are SYK, BTK and PI3Kδ (Figure 2).
B-cell receptor-signaling targets of inhibitors in clinical use. BLNK: B-cell linker protein; BTK: Bruton's tyrosine kinase; FosD: Fostamatinib disodium; PIP3: Phosphatidylinositol-3,4,5-triphosphate; PLCγ2: Phospholipase-Cγ2; SYK: spleen tyrosine kinase.
The only SYK inhibitor in clinical use to date is R788 (fostamatinib disodium [FosD]). Fostamatinib is a prodrug that is rapidly converted in vivo into bioactive form, R406.[60,68] Promising results have been obtained in B-CLL using fostamatinib in a Phase I/II study. However, fostamatinib use has been developed in rheumatoid arthritis, where it is being tested in a Phase III trail, but no SYK inhibitors are currently being used in patients with B-CLL.
BTK is a nonreceptor kinase of the Tec family that plays a key role in B-cell proliferation and differentiation. In addition, BTK is part of the signaling network downstream of the CXCR4 and CXCR5 chemokine receptors and integrins, which are central to B-cell trafficking and tissue homing.[70,71] It is specifically inhibited by PCI-32765, which blocks BTK phosphorylation and consequently its enzymatic activity. PCI-32765 has shown encouraging clinical results in patients with B-cell malignancy, particularly in patients with B-CLL.[73–75] Response to PCI-32765 treatment is characterized by a rapid reduction in lympho-adenopathy and/or organomegaly, associated with a transient lymphocytosis. Interestingly, recent evidence has shown that PCI-32765 significantly inhibits B-CLL cell proliferation, migration and survival in response to various physiological stimuli both in in vitro and in vivo mouse models, which could explain some of the characteristic clinical activity of this therapeutic agent.[76,77] Furthermore, PCI-32765 inhibits the BCR and chemokine receptor-mediated signaling pathways and secretion of chemokines (CCL3 and CCL4) mediated by BCR activity. The inhibition of migration and homing processes by PCI-32765 may be the basis of the early efflux of B-CLL cells from tissue into the blood and the consequent lymphocytosis.
CAL-101 is a potent and highly selective inhibitor of PI3Kδ, the PI3K isoform that plays a critical role in B-cell functions mediated by the BCR signaling. CAL-101 induces apoptosis in B-cell lines and primary cells from patients with B-CLL, suggesting that this effect may underlie its clinical activity. However, CAL-101 promotes a transient lymphocytosis and a reduction in lymphadenopathy in patients during the first course of treatment. It was recently shown that CAL-101 inhibits B-CLL chemotaxis and migration beneath stromal cells. Taken together, these results suggest that CAL-101 acts via a dual mechanism of action: directly reducing cell survival and decreasing cell interactions that retain B-CLL cells in their microenvironments.
The similarity of clinical responses obtained following treatments with SYK, BTK or PI3Kδ inhibitors suggest that these kinases are nodal elements on the BCR signaling network, thus leading to overlapping biological readouts.
Using these kinase inhibitors as single therapeutic agents implies long time to remission. Future combination therapy with cytotoxic drugs may reduce the time of remission. Data from ongoing single-agent and combination trails with PCI-32765 and CAL-101 will provide useful insights for the optimal therapeutic use of these BCR signaling inhibitors in B-CLL.
Expert Rev Hematol. 2012;5(3):341-348. © 2012 Expert Reviews Ltd.