The pan phosphoinositide 3-kinase/mammalian target of rapamycin inhibitor SAR245409 (voxtalisib/XL765) blocks survival, adhesion and proliferation of primary chronic lymphocytic leukemia cells.
The phosphoinositide 3-kinases (PI3Ks) are critical components of the B-cell receptor (BCR) pathway and have an important role in the pathobiology of chronic lymphocytic leukemia (CLL). Inhibitors of PI3Kδ block BCR-mediated cross-talk between CLL cells and the lymph node microenvironment and provide significant clinical benefit to CLL patients. However, the PI3Kδ inhibitors applied thus far have limited direct impact on leukemia cell survival and thus are unlikely to eradicate the disease. The use of inhibitors of multiple isoforms of PI3K might lead to deeper remissions. Here we demonstrate that the pan-PI3K/mammalian target of rapamycin inhibitor SAR245409 (voxtalisib/XL765) was more pro-apoptotic to CLL cells--irrespective of their ATM/p53 status--than PI3Kα or PI3Kδ isoform selective inhibitors. Furthermore, SAR245409 blocked CLL survival, adhesion and proliferation. Moreover, SAR245409 was a more potent inhibitor of T-cell-mediated production of cytokines, which support CLL survival. Taken together, our in vitro data provide a rationale for the evaluation of a pan-PI3K inhibitor in CLL patients.
Department of Experimental Immunology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.|Department of Hematology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.|Lymphoma and Myeloma Center Amsterdam, LYMMCARE, Amsterdam, The Netherlands.
R
R
Thijssen
Department of Experimental Immunology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.|Department of Hematology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.|Lymphoma and Myeloma Center Amsterdam, LYMMCARE, Amsterdam, The Netherlands.
J
J
Ter Burg
Department of Experimental Immunology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.|Department of Hematology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
G G W
GG
van Bochove
Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
M F M
MF
de Rooij
Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
A
A
Kuil
Department of Experimental Immunology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
M H
MH
Jansen
Department of Blood Cell Research, Sanquin Research and Landsteiner Laboratory, Amsterdam, The Netherlands.|Department of Pediatric Hematology, Immunology and Infectious Diseases, Emma Children's Hospital, Academic Medical Center, Amsterdam, The Netherlands.
T W
TW
Kuijpers
Department of Medical Oncology, Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands.
J W
JW
Baars
Cancer Biology, Sanofi Oncology, Vitry/Seine, France.
A
A
Virone-Oddos
Lymphoma and Myeloma Center Amsterdam, LYMMCARE, Amsterdam, The Netherlands.|Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
M
M
Spaargaren
Translational Medicine, Sanofi Oncology, Vitry/Seine, France.
C
C
Egile
Department of Hematology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.|Lymphoma and Myeloma Center Amsterdam, LYMMCARE, Amsterdam, The Netherlands.
M H J
MH
van Oers
Department of Experimental Immunology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.|Lymphoma and Myeloma Center Amsterdam, LYMMCARE, Amsterdam, The Netherlands.
E
E
Eldering
Department of Hematology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.|Lymphoma and Myeloma Center Amsterdam, LYMMCARE, Amsterdam, The Netherlands.
M J
MJ
Kersten
Department of Hematology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.|Lymphoma and Myeloma Center Amsterdam, LYMMCARE, Amsterdam, The Netherlands.
A P
AP
Kater
D000293:Adolescent; D000328:Adult; D019013:CD40 Antigens / Q000502:physiology; D002448:Cell Adhesion / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D016207:Cytokines / Q000096:biosynthesis; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000473:pathology; D008875:Middle Aged; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011687:Purines / Q000494:pharmacology; D052999:Quinazolinones / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology*; D013449:Sulfonamides / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000276:immunology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*
D019013:CD40 Antigens; D016207:Cytokines; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011687:Purines; D052999:Quinazolinones; D011810:Quinoxalines; D013449:Sulfonamides; C576808:XL765; D058570:TOR Serine-Threonine Kinases; C552946:idelalisib