Targeting SHIP1 and SHIP2 in Cancer

SIMPLE SUMMARY: Phosphoinositol signaling pathways and their dysregulation have been shown to have a fundamental role in health and disease, respectively. The SH2-containing 5′ inositol phosphatases, SHIP1 and SHIP2, are regulators of the PI3K/AKT pathway that have crucial roles in cancer progression. This review aims to summarize the role of SHIP1 and SHIP2 in cancer signaling and the immune response to cancer, the discovery and use of SHIP inhibitors and agonists as possible cancer therapeutics. ABSTRACT: Membrane-anchored and soluble inositol phospholipid species are critical mediators of intracellular cell signaling cascades. Alterations in their normal production or degradation are implicated in the pathology of a number of disorders including cancer and pro-inflammatory conditions. The SH2-containing 5′ inositol phosphatases, SHIP1 and SHIP2, play a fundamental role in these processes by depleting PI(3,4,5)P(3), but also by producing PI(3,4)P(2) at the inner leaflet of the plasma membrane. With the intent of targeting SHIP1 or SHIP2 selectively, or both paralogs simultaneously, small molecule inhibitors and agonists have been developed and tested in vitro and in vivo over the last decade in various disease models. These studies have shown promising results in various pre-clinical models of disease including cancer and tumor immunotherapy. In this review the potential use of SHIP inhibitors in cancer is discussed with particular attention to the molecular structure, binding site and efficacy of these SHIP inhibitors.