| RRC ID |
45452
|
| 著者 |
Balakrishnan K, Peluso M, Fu M, Rosin NY, Burger JA, Wierda WG, Keating MJ, Faia K, O'Brien S, Kutok JL, Gandhi V.
|
| タイトル |
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.
|
| ジャーナル |
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.
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| 巻・号 |
29(9)
|
| ページ |
1811-22
|
| 公開日 |
2015-9-1
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| DOI |
10.1038/leu.2015.105
|
| PII |
leu2015105
|
| PMID |
25917267
|
| PMC |
PMC4558374
|
| MeSH |
Adenine / analogs & derivatives
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 / metabolism*
Phosphoinositide-3 Kinase Inhibitors*
Phosphorylation
Piperidines
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 |
8.665
|
| 引用数 |
88
|
|
WOS 分野
|
ONCOLOGY
HEMATOLOGY
|
| リソース情報 |
| ヒト・動物細胞 |
StromaNKtert(RCB2350) |
