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

• Published in: Blood 2014-12, Vol.124 (24), p.3583-3586
• Main Authors: Dong, Shuai, Guinn, Daphne, Dubovsky, Jason A., Zhong, Yiming, Lehman, Amy, Kutok, Jeffery, Woyach, Jennifer A., Byrd, John C., Johnson, Amy J.
• Format: Article
• Language: English
• Subjects: Agammaglobulinaemia Tyrosine Kinase; Amino Acid Substitution; Antineoplastic Agents - pharmacology; B-Lymphocytes - enzymology; B-Lymphocytes - pathology; Brief Report; 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; Lymphoid Neoplasia; Male; Mutation, Missense; Neoplasm Proteins - antagonists & inhibitors; Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; 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
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2014-07-587279

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. •PI3K p110δ/γ inhibitor IPI-145 abrogates prosurvival signals and induces apoptosis in CLL cells.•IPI-145 overcomes BTK C481S mutation conferring ibrutinib resistance.