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Chronic lymphocytic leukemia

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 volume 30, pages 337–345 (2016)Cite this article

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A Corrigendum to this article was published on 07 September 2016

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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Acknowledgements

We thank the CLL patients for their blood donations and Marjolein Spiering and Dieuwertje Luijks for database management and CLL cell phenotyping. APK is a recipient of a Dutch Cancer Society Clinical Fellowship.

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  1. M J Kersten and A P Kater: These authors share last authorship on the paper.

Authors and Affiliations

  1. Department of Experimental Immunology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

    R Thijssen, J ter Burg, G G W van Bochove, M H Jansen & E Eldering

  2. Department of Hematology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

    R Thijssen, J ter Burg, G G W van Bochove, M H J van Oers, M J Kersten & A P Kater

  3. Lymphoma and Myeloma Center Amsterdam, LYMMCARE, Amsterdam, The Netherlands

    R Thijssen, J ter Burg, M Spaargaren, M H J van Oers, E Eldering, M J Kersten & A P Kater

  4. Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

    M F M de Rooij, A Kuil & M Spaargaren

  5. Department of Blood Cell Research, Sanquin Research and Landsteiner Laboratory, Amsterdam, The Netherlands

    T W Kuijpers

  6. Department of Pediatric Hematology, Immunology and Infectious Diseases, Emma Children’s Hospital, Academic Medical Center, Amsterdam, The Netherlands

    T W Kuijpers

  7. Department of Medical Oncology, Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands

    J W Baars

  8. Cancer Biology, Sanofi Oncology, Vitry/Seine, France

    A Virone-Oddos

  9. Translational Medicine, Sanofi Oncology, Vitry/Seine, France

    C Egile

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  1. R Thijssen
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Thijssen, R., ter Burg, J., van Bochove, G. et al. 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 30, 337–345 (2016). https://doi.org/10.1038/leu.2015.241

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