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The pan phosphoinositide 3-kinase/mammalian target of rapamycin inhibitor SAR245409 (voxtalisib/XL765) blocks survival, adhesion and proliferation of primary chronic lymphocytic leukemia cells. / Thijssen, R.; ter Burg, J.; van Bochove, G. G. W. et al.

In: Leukemia, Vol. 30, No. 2, 2016, p. 337-345.

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@article{e1dd597978b341b1b9ae627cb907c11e,
title = "The pan phosphoinositide 3-kinase/mammalian target of rapamycin inhibitor SAR245409 (voxtalisib/XL765) blocks survival, adhesion and proliferation of primary chronic lymphocytic leukemia cells",
abstract = "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",
author = "R. Thijssen and {ter Burg}, J. and {van Bochove}, {G. G. W.} and {de Rooij}, {M. F. M.} and A. Kuil and Jansen, {M. H.} and Kuijpers, {T. W.} and Baars, {J. W.} and A. Virone-Oddos and M. Spaargaren and C. Egile and {van Oers}, {M. H. J.} and E. Eldering and Kersten, {M. J.} and Kater, {A. P.}",
year = "2016",
doi = "10.1038/leu.2015.241",
language = "English",
volume = "30",
pages = "337--345",
journal = "Leukemia",
issn = "0887-6924",
publisher = "Nature Publishing Group",
number = "2",

}

RIS

TY - JOUR

T1 - The pan phosphoinositide 3-kinase/mammalian target of rapamycin inhibitor SAR245409 (voxtalisib/XL765) blocks survival, adhesion and proliferation of primary chronic lymphocytic leukemia cells

AU - Thijssen, R.

AU - ter Burg, J.

AU - van Bochove, G. G. W.

AU - de Rooij, M. F. M.

AU - Kuil, A.

AU - Jansen, M. H.

AU - Kuijpers, T. W.

AU - Baars, J. W.

AU - Virone-Oddos, A.

AU - Spaargaren, M.

AU - Egile, C.

AU - van Oers, M. H. J.

AU - Eldering, E.

AU - Kersten, M. J.

AU - Kater, A. P.

PY - 2016

Y1 - 2016

N2 - 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

AB - 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

U2 - 10.1038/leu.2015.241

DO - 10.1038/leu.2015.241

M3 - Article

C2 - 26338274

VL - 30

SP - 337

EP - 345

JO - Leukemia

JF - Leukemia

SN - 0887-6924

IS - 2

ER -

ID: 2690223