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

Leukemia
R ThijssenA P Kater

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.

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Citations

Feb 9, 2018·Cellular and Molecular Life Sciences : CMLS·Jin ZhangBo Liu
Sep 13, 2019·The Journal of Immunology : Official Journal of the American Association of Immunologists·Tom HoflandEric Eldering
Feb 9, 2020·International Journal of Molecular Sciences·Chiara TarantelliFrancesco Bertoni
Aug 12, 2016·The Journal of Immunology : Official Journal of the American Association of Immunologists·Peter J SiskaJeffrey C Rathmell
Mar 23, 2019·ACS Chemical Biology·Maria ReineckeGuillaume Médard

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