John C. Byrd, MD, and Amy J. Johnson, PhD
Drs. Byrd and Johnson indicated no relevant conflicts of interest.
Ponader S, Chen S, Buggy JJ, et al. Bruton’s tyrosine kinase inhibitor PCI-32765 thwarts chronic lymphocytic leukemia cell survival and tissue homing in vitro and in vivo. Blood. 2011. Epub ahead of print.
A common finding in chronic lymphocytic leukemia (CLL) patients is constitutive activation of kinases associated with the B-cell receptor (BCR) signaling pathway. Several small-molecule inhibitors including GS-1101 that target Syk (splenic tyrosine kinase) and PCI-32765 that target BTK (Burton agammaglobulinemia tyrosine kinase) showed potential efficacy in preclinical testing based on their capacity to inhibit BCR signaling. These agents subsequently entered the clinical arena, and early experience indicated that they were ineffective in treating CLL based on worsening of peripheral blood lymphocytosis. Extended follow-up, however, proved otherwise. In some treated patients, lymphocytosis returned to pre-treatment baseline values, but more importantly, durable reduction in lymph node and spleen involvement and improvement in cytopenias was observed despite persistent lymphocytosis. In the current study, a collaborative effort involving the laboratories of Nicholas Chiorazzi (Feinstein Institute for Medical Research) and Jan Burger (MD Anderson Cancer Center), the mechanisms of action of PCI-32765 were investigated using both in vitro and in vivo models. PCI-32765 is an irreversible BTK inhibitor1 that has anti-apoptotic and anti-proliferative properties against CLL cells independent of microenvironment signals.2 This new paper extends the observation of the initial study by showing that CLL cell migration, proliferation on stromal cells, and adhesion are altered by PCI-32765 in vitro. Evidence of disrupted signaling is demonstrated in vivo in CLL patients, where plasma levels of the BCR-dependent chemokines CCL3 and CCL4 are rapidly reduced following initiation of PCI-32765 treatment. To study the effects of PCI-32765 in vivo, an adoptive transplant model was used.3 The particular TCL1 murine leukemia cells used in this system (TCL-192) were selected in part because they express a BCR that is reactive with phosphatidylcholine. Compared with mice treated with the vehicle control, PCI-32765-treated mice engrafted with TCL1 cells developed lymphocytosis initially; however, reduction in disease and improvement in overall survival were subsequently observed. Concordantly, inhibition of downstream BTK-activated targets was demonstrated.
Why are these results important? The inhibitors of BCR signaling are active in CLL, yet their effects on lymphocyte trafficking challenge our traditional way of assessing disease response in which finding an increase in lymphocytosis is seen as an indication of disease progression. PCI-32765-induced lymphocytosis appears to be a consequence of aberrant trafficking in which movement into compartments outside of the peripheral blood system is inhibited. Therefore, PCI-32765-induced lymphocytosis likely results from cellular redistribution rather than clonal expansion. The studies of Ponader et al. have expanded our understanding of the effects of inhibition of BCR signaling kinases on the properties of CLL cellsin vitro. Importantly, their adoptive transplant system appears to be a valid model for investigating the effects of these inhibitors in vivo. By incorporating use of genetically modified TCL1 cells, this model provides a tool for future studies aimed at teasing out the precise mechanisms by which inhibitors of BCR signaling kinases modulate lymphocyte trafficking. The inhibitors of BCR signaling kinases are an exciting new class of drugs for treatment of CLL, and the studies of Ponader and colleagues and others build upon our knowledge of how these agents work.
- Honigberg LA, Smith AM, Sirisawad M, et al. The Bruton tyrosine kinase inhibitor PCI-32765 blocks B-cell activation and is efficacious in models of autoimmune disease and B-cell malignancy. Proc Natl Acad Sci USA. 2010;107:13075-13080.
- Herman SE, Gordon AL, Hertlein E, et al. Bruton tyrosine kinase represents a promising therapeutic target for treatment of chronic lymphocytic leukemia and is effectively targeted by PCI-32765. Blood. 2011;117:6287-6296.
- Bichi R, Shinton SA, Martin ES, et al. Human chronic lymphocytic leukemia modeled in mouse by targeted TCL1 expression. Proc Natl Acad Sci USA. 2002;99:6955-6960.
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