The phosphoinositide 3'-kinase delta inhibitor, CAL-101, inhibits B-cell receptor signaling and chemokine networks in chronic lymphocytic leukemia.

Abstract

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.

• Authors: Julia Hoellenriegel, Sarah A Meadows, Mariela Sivina, William G Wierda, Hagop Kantarjian, Michael J Keating, Neill Giese, Susan O'Brien, Albert Yu, Langdon L Miller, Brian J Lannutti, Jan A Burger
• Journal: Blood (Blood) Vol. 118 Issue 13 Pg. 3603-12 (Sep 29 2011) ISSN: 1528-0020 [Electronic] United States
• PMID: 21803855 (Publication Type: Clinical Trial, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Chemokines
• Phosphoinositide-3 Kinase Inhibitors
• Purines
• Quinazolinones
• Receptors, Antigen, B-Cell
• Class I Phosphatidylinositol 3-Kinases
• PIK3CD protein, human
• idelalisib

Topics

• Antineoplastic Agents (therapeutic use)
• Cell Movement (drug effects)
• Cell Survival (drug effects)
• Cells, Cultured
• Chemokines (antagonists & inhibitors, metabolism)
• Class I Phosphatidylinositol 3-Kinases
• Down-Regulation (drug effects)
• Drug Evaluation, Preclinical
• Humans
• Leukemia, Lymphocytic, Chronic, B-Cell (drug therapy, metabolism, pathology)
• Metabolic Networks and Pathways (drug effects, physiology)
• Phosphoinositide-3 Kinase Inhibitors
• Purines (pharmacology, therapeutic use)
• Quinazolinones (pharmacology, therapeutic use)
• Receptors, Antigen, B-Cell (antagonists & inhibitors)
• Signal Transduction (drug effects)