title: PKC-β as a therapeutic target in CLL: PKC inhibitor AEB071 demonstrates preclinical activity in CLL.
abstract: Targeting B-cell receptor (BCR) signaling in chronic lymphocytic leukemia (CLL) has been successful with durable remissions observed with several targeted therapeutics. Protein kinase C-β (PKC-β) is immediately downstream of BCR and has been shown to be essential to CLL cell survival and proliferation in vivo. We therefore evaluated sotrastaurin (AEB071), an orally administered potent PKC inhibitor, on CLL cell survival both in vitro and in vivo. AEB071 shows selective cytotoxicity against B-CLL cells in a dose-dependent manner. Additionally, AEB071 attenuates BCR-mediated survival pathways, inhibits CpG-induced survival and proliferation of CLL cells in vitro, and effectively blocks microenvironment-mediated survival signaling pathways in primary CLL cells. Furthermore, AEB071 alters β-catenin expression, resulting in decreased downstream transcriptional genes as c-Myc, Cyclin D1, and CD44. Lastly, our preliminary in vivo studies indicate beneficial antitumor properties of AEB071 in CLL. Taken together, our results indicate that targeting PKC-β has the potential to disrupt signaling from the microenvironment contributing to CLL cell survival and potentially drug resistance. Future efforts targeting PKC with the PKC inhibitor AEB071 as monotherapy in clinical trials of relapsed and refractory CLL patients are warranted.
authors.affiliation: Division of Hematology, Department of Internal Medicine.
authors.forename: Dalia
authors.initials: D
authors.lastname: El-Gamal
authors.affiliation: Division of Hematology, Department of Internal Medicine.
authors.forename: Katie
authors.initials: K
authors.lastname: Williams
authors.affiliation: Division of Hematology, Department of Internal Medicine.
authors.forename: Taylor D
authors.initials: TD
authors.lastname: LaFollette
authors.affiliation: Division of Hematology, Department of Internal Medicine.
authors.forename: Matthew
authors.initials: M
authors.lastname: Cannon
authors.affiliation: Division of Hematology, Department of Internal Medicine.
authors.forename: James S
authors.initials: JS
authors.lastname: Blachly
authors.affiliation: Division of Hematology, Department of Internal Medicine.
authors.forename: Yiming
authors.initials: Y
authors.lastname: Zhong
authors.affiliation: Division of Hematology, Department of Internal Medicine.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Woyach
authors.affiliation: Division of Hematology, Department of Internal Medicine.
authors.forename: Erich
authors.initials: E
authors.lastname: Williams
authors.affiliation: Division of Hematology, Department of Internal Medicine.
authors.forename: Farrukh T
authors.initials: FT
authors.lastname: Awan
authors.affiliation: Division of Hematology, Department of Internal Medicine.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Jones
authors.affiliation: Division of Hematology, Department of Internal Medicine.
authors.forename: Leslie
authors.initials: L
authors.lastname: Andritsos
authors.affiliation: Division of Hematology, Department of Internal Medicine.
authors.forename: Kami
authors.initials: K
authors.lastname: Maddocks
authors.affiliation: Division of Medicinal Chemistry, College of Pharmacy, and.
authors.forename: Chia-Hsien
authors.initials: CH
authors.lastname: Wu
authors.affiliation: Division of Medicinal Chemistry, College of Pharmacy, and.
authors.forename: Ching-Shih
authors.initials: CS
authors.lastname: Chen
authors.affiliation: Center for Biostatistics, The Ohio State University, Columbus, OH.
authors.forename: Amy
authors.initials: A
authors.lastname: Lehman
authors.affiliation: Center for Biostatistics, The Ohio State University, Columbus, OH.
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Division of Hematology, Department of Internal Medicine.
authors.forename: Rosa
authors.initials: R
authors.lastname: Lapalombella
authors.affiliation: Division of Hematology, Department of Internal Medicine.
authors.forename: John C
authors.initials: JC
authors.lastname: Byrd
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D064546:Protein Kinase C beta / Q000037:antagonists & inhibitors*; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011758:Pyrroles / Q000627:therapeutic use*; D011799:Quinazolines / Q000627:therapeutic use*; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D059016:Tumor Microenvironment / Q000187:drug effects; D060449:Wnt Signaling Pathway / Q000187:drug effects; D051176:beta Catenin / Q000378:metabolism
chemical_list: C495270:CTNNB1 protein, human; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; D011799:Quinazolines; D011947:Receptors, Antigen, B-Cell; D051176:beta Catenin; C543528:sotrastaurin; D000071679:Glycogen Synthase Kinase 3 beta; D064546:Protein Kinase C beta; D038362:Glycogen Synthase Kinase 3; D013755:Tetradecanoylphorbol Acetate