Phosphatidylinositol-3 kinase (PI3K) signaling is activated in various subtypes of B-cell neoplasms where it is an important driver of proliferation and survival of malignant cells. PI3K inhibitors have been introduced into clinical practice, however, there remains a clear need for new drug strategies to target PI3K signaling. For example, treatment with the PI3Kδ-specific inhibitor idelalisib can be associated with substantial toxicity and idelalisib is relatively ineffective as a monotherapy in diffuse large B cell lymphoma (DLBCL). PI3K activity is naturally countered by the inositol lipid phosphatase SHIP1 and, in this study, we show that the novel chemical SHIP1 activator AQX-435 effectively inhibited PI3K signaling in both primary chronic lymphocytic cells and DLBCL-derived cell lines, and reduced growth of lymphoma in vivo, alone and in combination with the BTK inhibitor ibrutinib. Thus, SHIP1 activation may present a novel paradigm to inhibit PI3K signaling in B-cell neoplasms.
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