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The phosphoinositide 3′-kinase delta inhibitor, CAL-101, inhibits B-cell receptor signaling and chemokine networks in chronic lymphocytic leukemia
Open accessAbstract
In lymphocytes, the phosphoinositide 3′-kinase (PI3K) isoform p110δ (PI3Kδ) transmits signals from surface receptors, including the B-cell receptor (BCR). CAL-101, a selective inhibitor of PI3Kδ, displays clinical activity in CLL, causing rapid lymph node shrinkage and a transient lymphocytosis. Inhibition of pro-survival pathways, the presumed mechanism of CAL-101, does not explain this characteristic pattern of activity. Therefore, we tested CAL-101 in assays that model CLL-microenvironment interactions in vitro. We found that CAL-101 inhibits CLL cell chemotaxis toward CXCL12 and CXCL13 and migration beneath stromal cells (pseudoemperipolesis). CAL-101 also down-regulates secretion of chemokines in stromal cocultures and after BCR triggering. CAL-101 reduces survival signals derived from the BCR or from nurse-like cells, and inhibits BCR- and chemokine-receptor–induced AKT and MAP kinase (ERK) activation. In stromal cocultures, CAL-101 sensitizes CLL cells toward bendamustine, fludarabine, and dexamethasone. These results are corroborated by clinical data showing marked reductions in circulating CCL3, CCL4, and CXCL13 levels, and a surge in lymphocytosis during CAL-101 treatment. Thus, CAL-101 displays a dual mechanism of action, directly decreasing cell survival while reducing interactions that retain CLL cells in protective tissue microenvironments. These data provide an explanation for the clinical activity of CAL-101, and a roadmap for future therapeutic development.
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Metadata
- Authors
- Hoellenriegel, J., Meadows, S. A., Sivina, M., Wierda, W. G., Kantarjian, H., Keating, M. J., Giese, N., O'Brien, S., Yu, A., Miller, L. L., Lannutti, B. J., & Burger, J. A.
- Venue
- Blood
- Publisher
- American Society of Hematology
- Published
- 2011-09-29
- Volume
- 118
- Issue
- 13
- Pages
- 3603-3612
- ISSN
- 0006-4971 (ISSN-L)
- 1528-0020
- OpenAlex
- W2038053631
- Cited by
- 549
- References
- 0
- FWCI
- 30.62
- Type
- journal article
- Language
- en
- Open access
- green
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