IPI-145 antagonizes intrinsic and extrinsic survival signals in chronic lymphocytic leukemia cells

Blood. 2014 Dec 4;124(24):3583-6. doi: 10.1182/blood-2014-07-587279. Epub 2014 Sep 25.

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.

Publication types

  • Clinical Trial
  • Research Support, N.I.H., Extramural

MeSH terms

  • Adenine / analogs & derivatives
  • Agammaglobulinaemia Tyrosine Kinase
  • Amino Acid Substitution
  • Antineoplastic Agents / pharmacology*
  • B-Lymphocytes / enzymology
  • B-Lymphocytes / pathology
  • Cell Survival / drug effects
  • Cell Survival / genetics
  • Class I Phosphatidylinositol 3-Kinases / antagonists & inhibitors*
  • Class I Phosphatidylinositol 3-Kinases / genetics
  • Class I Phosphatidylinositol 3-Kinases / metabolism
  • Class Ib Phosphatidylinositol 3-Kinase / genetics
  • Drug Resistance, Neoplasm / drug effects
  • Drug Resistance, Neoplasm / genetics
  • Enzyme Inhibitors / pharmacology*
  • Female
  • Humans
  • Isoquinolines / pharmacology*
  • Killer Cells, Natural / enzymology
  • Killer Cells, Natural / pathology
  • Leukemia, Lymphocytic, Chronic, B-Cell / drug therapy*
  • Leukemia, Lymphocytic, Chronic, B-Cell / enzymology
  • Leukemia, Lymphocytic, Chronic, B-Cell / genetics
  • Leukemia, Lymphocytic, Chronic, B-Cell / pathology
  • Male
  • Mutation, Missense
  • Neoplasm Proteins / antagonists & inhibitors*
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism
  • Piperidines
  • Protein-Tyrosine Kinases / genetics
  • Protein-Tyrosine Kinases / metabolism
  • Purines / pharmacology*
  • Pyrazoles / pharmacology
  • Pyrimidines / pharmacology
  • Signal Transduction / drug effects*
  • Signal Transduction / genetics
  • T-Lymphocytes / enzymology
  • T-Lymphocytes / pathology
  • Tumor Cells, Cultured

Substances

  • Antineoplastic Agents
  • Enzyme Inhibitors
  • Isoquinolines
  • Neoplasm Proteins
  • Piperidines
  • Purines
  • Pyrazoles
  • Pyrimidines
  • ibrutinib
  • duvelisib
  • Class I Phosphatidylinositol 3-Kinases
  • Class Ib Phosphatidylinositol 3-Kinase
  • PIK3CD protein, human
  • PIK3CG protein, human
  • Protein-Tyrosine Kinases
  • Agammaglobulinaemia Tyrosine Kinase
  • BTK protein, human
  • Adenine