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Chronic lymphocytic leukemia

The phosphoinositide-3-kinase (PI3K)-delta and gamma inhibitor, IPI-145 (Duvelisib), overcomes signals from the PI3K/AKT/S6 pathway and promotes apoptosis in CLL

Leukemia volume 29, pages 1811–1822 (2015)Cite this article

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Abstract

The functional relevance of the B-cell receptor (BCR) and the evolution of protein kinases as therapeutic targets have recently shifted the paradigm for treatment of B-cell malignancies. Inhibition of p110δ with idelalisib has shown clinical activity in chronic lymphocytic leukemia (CLL). The dynamic interplay of isoforms p110δ and p110γ in leukocytes support the hypothesis that dual blockade may provide a therapeutic benefit. IPI-145, an oral inhibitor of p110δ and p110γ isoforms, sensitizes BCR-stimulated and/or stromal co-cultured primary CLL cells to apoptosis (median 20%, n=57; P<0.0001) including samples with poor prognostic markers, unmutated IgVH (n=28) and prior treatment (n=15; P<0.0001). IPI-145 potently inhibits the CD40L/IL-2/IL-10 induced proliferation of CLL cells with an IC50 in sub-nanomolar range. A corresponding dose-responsive inhibition of pAKTSer473 is observed with an IC50 of 0.36 nM. IPI-145 diminishes the BCR-induced chemokines CCL3 and CCL4 secretion to 17% and 37%, respectively. Pre-treatment with 1 μM IPI-145 inhibits the chemotaxis toward CXCL12; reduces pseudoemperipolesis to median 50%, inferring its ability to interfere with homing capabilities of CLL cells. BCR-activated signaling proteins AKTSer473, BADSer112, ERKThr202/Tyr204 and S6Ser235/236 are mitigated by IPI-145. Importantly, for clinical development in hematological malignancies, IPI-145 is selective to CLL B cells, sparing normal B- and T-lymphocytes.

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Acknowledgements

The authors thank Benjamin Hayes for coordinating the blood sample collection and Susan C Smith for providing information on patient characteristics. This work was supported in part by an SRA from Infinity Pharmaceuticals, CLL PO1 CA81534, and K23 CA178183-01 from the National Cancer Institute. KB, WGW and VG are members of the CLL Research Consortium.

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Authors and Affiliations

  1. Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    K Balakrishnan & V Gandhi

  2. Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    K Balakrishnan, M Fu, N Y Rosin, J A Burger, W G Wierda, M J Keating, S O'Brien & V Gandhi

  3. Infinity Pharmaceuticals Inc., Cambridge, MA, USA

    M Peluso, K Faia & J L Kutok

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KB has a sponsored research agreement with Infinity Pharmaceuticals. MP, KF and JLK are employees of Infinity Pharmaceuticals. The remaining authors declare no conflict of interest.

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Balakrishnan, K., Peluso, M., Fu, M. et al. The phosphoinositide-3-kinase (PI3K)-delta and gamma inhibitor, IPI-145 (Duvelisib), overcomes signals from the PI3K/AKT/S6 pathway and promotes apoptosis in CLL. Leukemia 29, 1811–1822 (2015). https://doi.org/10.1038/leu.2015.105

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