title: 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.affiliation: Department of Leukemia, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA. jaburger@mdanderson.org
authors.forename: Julia
authors.initials: J
authors.lastname: Hoellenriegel
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Meadows
authors.forename: Mariela
authors.initials: M
authors.lastname: Sivina
authors.forename: William G
authors.initials: WG
authors.lastname: Wierda
authors.forename: Hagop
authors.initials: H
authors.lastname: Kantarjian
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Keating
authors.forename: Neill
authors.initials: N
authors.lastname: Giese
authors.forename: Susan
authors.initials: S
authors.lastname: O'Brien
authors.forename: Albert
authors.initials: A
authors.lastname: Yu
authors.forename: Langdon L
authors.initials: LL
authors.lastname: Miller
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Lannutti
authors.forename: Jan A
authors.initials: JA
authors.lastname: Burger
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D018925:Chemokines / Q000037:antagonists & inhibitors* / Q000378:metabolism; D058534:Class I Phosphatidylinositol 3-Kinases; D015536:Down-Regulation / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D053858:Metabolic Networks and Pathways / Q000187:drug effects / Q000502:physiology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011687:Purines / Q000494:pharmacology* / Q000627:therapeutic use; D052999:Quinazolinones / Q000494:pharmacology* / Q000627:therapeutic use; D011947:Receptors, Antigen, B-Cell / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D018925:Chemokines; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011687:Purines; D052999:Quinazolinones; D011947:Receptors, Antigen, B-Cell; D058534:Class I Phosphatidylinositol 3-Kinases; C486018:PIK3CD protein, human; C552946:idelalisib