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.
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.
Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.|Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
K
K
Balakrishnan
Infinity Pharmaceuticals Inc., Cambridge, MA, USA.
M
M
Peluso
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
M
M
Fu
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
N Y
NY
Rosin
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
J A
JA
Burger
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
W G
WG
Wierda
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
M J
MJ
Keating
Infinity Pharmaceuticals Inc., Cambridge, MA, USA.
K
K
Faia
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
S
S
O'Brien
Infinity Pharmaceuticals Inc., Cambridge, MA, USA.
J L
JL
Kutok
Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.|Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
V
V
Gandhi
D000225:Adenine / Q000031:analogs & derivatives; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis / Q000187:drug effects*; D001854:Bone Marrow Cells / Q000378:metabolism; D016022:Case-Control Studies; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects / Q000276:immunology; D054405:Chemokine CCL3 / Q000378:metabolism; D054407:Chemokine CCL4 / Q000378:metabolism; D002633:Chemotaxis / Q000187:drug effects / Q000276:immunology; D005260:Female; D006801:Humans; D007546:Isoquinolines / Q000494:pharmacology*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism*; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D010880:Piperidines; D011379:Prognosis; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D011687:Purines / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D052999:Quinazolinones / Q000494:pharmacology; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D017154:Stromal Cells / Q000378:metabolism
D000225:Adenine; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D007546:Isoquinolines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010880:Piperidines; D051057:Proto-Oncogene Proteins c-akt; D011687:Purines; D011720:Pyrazoles; D011743:Pyrimidines; D052999:Quinazolinones; D011947:Receptors, Antigen, B-Cell; D019893:Ribosomal Protein S6 Kinases; C551803:ibrutinib; C586691:duvelisib; C552946:idelalisib