Lemm, Elizabeth A., Valle-Argos, Beatriz, Smith, Lindsay D., Richter, Johanna, Gebreselassie, Yohannes, Carter, Mathew J., Karolova, Jana, Svaton, Michael, Helman, Karel, Weston-Bell, Nicola J., Karydis, Laura, Williamson, Chris T., Lenz, Georg, Pettigrew, Jeremy, Harwig, Curtis, Stevenson, Freda K., Cragg, Mark, Forconi, Francesco, Steele, Andrew J., Cross, Jennifer, Mackenzie, Lloyd, Klener, Pavel and Packham, Graham (2019) Preclinical evaluation of a novel SHIP1 phosphatase activator for inhibition of PI3K signaling in malignant B-cells. Clinical Cancer Research. (doi:10.1158/1078-0432.CCR-19-2202).
Abstract
PURPOSE: Phosphatidylinositol-3 kinase (PI3K) signaling is a common feature of B-cell neoplasms, including chronic lymphocytic leukemia (CLL) and diffuse large B-cell lymphoma (DLBCL), and PI3K inhibitors have been introduced into the clinic. However, there remains a clear need to develop new strategies to target PI3K signaling. PI3K activity is countered by Src homology domain 2-containing inositol-5'-phosphatase1 (SHIP1) and, here, we have characterized the activity of a novel SHIP1 activator, AQX-435, in pre-clinical models of B-cell malignancies.
EXPERIMENTAL DESIGN: In vitro activity of AQX-435 was evaluated using primary CLLcellsand DLBCL-derived cell lines. In vivo activity of AQX-435, alone or in combination with the BTK inhibitor ibrutinib, was assessed using DLBCL cell line and patient-derived xenograft models.
RESULTS: Pharmacological activation of SHIP1 using AQX-435 was sufficient to inhibit anti-IgM-induced PI3K-mediated signaling, including induction of AKT phosphorylation and MYC expression, without effects on upstream SYK phosphorylation. AQX-435 also co-operated with the BTK inhibitor ibrutinib to enhance inhibition of anti-IgM-induced AKT phosphorylation. AQX-435 induced caspase-dependent apoptosis of CLL cells preferentially as compared to normal B cells, and overcame in vitro survival promoting effects of microenvironmental stimuli. Finally, AQX-435 reduced AKT phosphorylation and growth of DLBCL in vivo,and co-operated with ibrutinib for tumor growth inhibition.
CONCLUSIONS: Our results using AQX-435 demonstrate that SHIP1 activation may be an effective novel therapeutic strategy for treatment of B-cell neoplasms, alone or in combination with ibrutinib.
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