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


Ontology type: schema:ScholarlyArticle     


Article Info

DATE

2016-02

AUTHORS

R Thijssen, J Ter Burg, G G W van Bochove, M F M de Rooij, A Kuil, M H Jansen, T W Kuijpers, J W Baars, A Virone-Oddos, M Spaargaren, C Egile, M H J van Oers, E Eldering, M J Kersten, A 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. More... »

PAGES

337

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/leu.2015.241

DOI

http://dx.doi.org/10.1038/leu.2015.241

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1035247117

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/26338274


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