RRC ID 45452
Author Balakrishnan K, Peluso M, Fu M, Rosin NY, Burger JA, Wierda WG, Keating MJ, Faia K, O'Brien S, Kutok JL, Gandhi V.
Title The phosphoinositide-3-kinase (PI3K)-delta and gamma inhibitor, IPI-145 (Duvelisib), overcomes signals from the PI3K/AKT/S6 pathway and promotes apoptosis in CLL.
Journal Leukemia
Abstract The functional relevance of the B-cell receptor (BCR) and the evolution of protein kinases as therapeutic targets have recently shifted the paradigm for treatment of B-cell malignancies. Inhibition of p110δ with idelalisib has shown clinical activity in chronic lymphocytic leukemia (CLL). The dynamic interplay of isoforms p110δ and p110γ in leukocytes support the hypothesis that dual blockade may provide a therapeutic benefit. IPI-145, an oral inhibitor of p110δ and p110γ isoforms, sensitizes BCR-stimulated and/or stromal co-cultured primary CLL cells to apoptosis (median 20%, n=57; P<0.0001) including samples with poor prognostic markers, unmutated IgVH (n=28) and prior treatment (n=15; P<0.0001). IPI-145 potently inhibits the CD40L/IL-2/IL-10 induced proliferation of CLL cells with an IC50 in sub-nanomolar range. A corresponding dose-responsive inhibition of pAKT(Ser473) is observed with an IC50 of 0.36 nM. IPI-145 diminishes the BCR-induced chemokines CCL3 and CCL4 secretion to 17% and 37%, respectively. Pre-treatment with 1 μM IPI-145 inhibits the chemotaxis toward CXCL12; reduces pseudoemperipolesis to median 50%, inferring its ability to interfere with homing capabilities of CLL cells. BCR-activated signaling proteins AKT(Ser473), BAD(Ser112), ERK(Thr202/Tyr204) and S6(Ser235/236) are mitigated by IPI-145. Importantly, for clinical development in hematological malignancies, IPI-145 is selective to CLL B cells, sparing normal B- and T-lymphocytes.
Volume 29(9)
Pages 1811-22
Published 2015-9
DOI 10.1038/leu.2015.105
PII leu2015105
PMID 25917267
PMC PMC4558374
MeSH Aged Aged, 80 and over Apoptosis / drug effects* Bone Marrow Cells / metabolism Case-Control Studies Cell Proliferation / drug effects Cell Survival / drug effects Cell Survival / immunology Chemokine CCL3 / metabolism Chemokine CCL4 / metabolism Chemotaxis / drug effects Chemotaxis / immunology Female Humans Isoquinolines / pharmacology* Leukemia, Lymphocytic, Chronic, B-Cell / diagnosis Leukemia, Lymphocytic, Chronic, B-Cell / genetics Leukemia, Lymphocytic, Chronic, B-Cell / metabolism* Leukocytes, Mononuclear / drug effects Leukocytes, Mononuclear / metabolism Male Middle Aged Phosphatidylinositol 3-Kinases / antagonists & inhibitors* Phosphatidylinositol 3-Kinases / metabolism* Phosphorylation Prognosis Proto-Oncogene Proteins c-akt / metabolism* Purines / pharmacology* Pyrazoles / pharmacology Pyrimidines / pharmacology Quinazolinones / pharmacology Receptors, Antigen, B-Cell / metabolism Ribosomal Protein S6 Kinases / metabolism* Signal Transduction / drug effects* Stromal Cells / metabolism
IF 9.944
Times Cited 22
Human and Animal Cells