title: IPI-145 antagonizes intrinsic and extrinsic survival signals in chronic lymphocytic leukemia cells.
abstract: Chronic lymphocytic leukemia (CLL) displays constitutive phosphatidylinositol 3-kinase (PI3K) activation resulting from aberrant regulation of B-cell receptor (BCR) signaling. Previous studies have shown that an oral PI3K p110δ inhibitor idelalisib exhibits promising activity in CLL. Here, we demonstrate that a dual PI3K p110δ and p110γ inhibitor, IPI-145, antagonizes BCR crosslinking activated prosurvival signals in primary CLL cells. IPI-145 causes direct killing in primary CLL cells in a dose- and time-dependent fashion, but does not generate direct cytotoxicity to normal B cells. However, IPI-145 does reduce the viability of normal T and natural killer cells and decrease activated T-cell production of various inflammatory and antiapoptotic cytokines. Furthermore, IPI-145 overcomes the ibrutinib resistance resulting from treatment-induced BTK C481S mutation. Collectively, these studies provide rationale for ongoing clinical evaluation of IPI-145 as a targeted therapy for CLL and related B-cell lymphoproliferative disorders.
authors.affiliation: Division of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy.
authors.forename: Shuai
authors.initials: S
authors.lastname: Dong
authors.affiliation: Biomedical Sciences Graduate Program, College of Medicine.
authors.forename: Daphne
authors.initials: D
authors.lastname: Guinn
authors.affiliation: Division of Hematology, Department of Internal Medicine and Comprehensive Cancer Center, and.
authors.forename: Jason A
authors.initials: JA
authors.lastname: Dubovsky
authors.affiliation: Division of Hematology, Department of Internal Medicine and Comprehensive Cancer Center, and.
authors.forename: Yiming
authors.initials: Y
authors.lastname: Zhong
authors.affiliation: Center for Biostatistics, The Ohio State University, Columbus, OH;
authors.forename: Amy
authors.initials: A
authors.lastname: Lehman
authors.affiliation: Infinity Pharmaceuticals Inc., Cambridge, MA; and.
authors.forename: Jeffery
authors.initials: J
authors.lastname: Kutok
authors.affiliation: Division of Hematology, Department of Internal Medicine and Comprehensive Cancer Center, and.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Woyach
authors.affiliation: Division of Hematology, Department of Internal Medicine and Comprehensive Cancer Center, and Division of Medicinal Chemistry, College of Pharmacy, The Ohio State University, Columbus, OH.
authors.forename: John C
authors.initials: JC
authors.lastname: Byrd
authors.affiliation: Division of Hematology, Department of Internal Medicine and Comprehensive Cancer Center, and Division of Medicinal Chemistry, College of Pharmacy, The Ohio State University, Columbus, OH.
authors.forename: Amy J
authors.initials: AJ
authors.lastname: Johnson
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives; D000077329:Agammaglobulinaemia Tyrosine Kinase; D019943:Amino Acid Substitution; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001402:B-Lymphocytes / Q000201:enzymology / Q000473:pathology; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D058534:Class I Phosphatidylinositol 3-Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D058544:Class Ib Phosphatidylinositol 3-Kinase / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007546:Isoquinolines / Q000494:pharmacology*; D007694:Killer Cells, Natural / Q000201:enzymology / Q000473:pathology; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D008297:Male; D020125:Mutation, Missense; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D010880:Piperidines; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D011687:Purines / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics; D013601:T-Lymphocytes / Q000201:enzymology / Q000473:pathology; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D007546:Isoquinolines; D009363:Neoplasm Proteins; D010880:Piperidines; D011687:Purines; D011720:Pyrazoles; D011743:Pyrimidines; C551803:ibrutinib; C586691:duvelisib; D058534:Class I Phosphatidylinositol 3-Kinases; D058544:Class Ib Phosphatidylinositol 3-Kinase; C486018:PIK3CD protein, human; C546760:PIK3CG protein, human; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human; D000225:Adenine