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• W2949384612 abstract "Introduction: Mantle cell lymphoma (MCL) is a rare B-cell non-Hodgkin lymphoma (NHL) that is aggressive and incurable with existing therapies, presenting a significant unmet clinical need. New treatment strategies that are based upon functional understanding of distinctive features associated with the malignant cells of this disease are required. Methods: Tissue microarrays from B-cell NHLs were analysed by immunohistochemistry and RNAScope for the expression of PI3Kγ. The function of PI3Kγ in MCL was examined using MAVER-1 and JEKO-1 cells and in malignant lymphocytes from patients with MCL. We examined the effects of specific inhibitors of PI3Kα (A66), PI3Kγ (CZC24832), and PI3Kδ (idelalisib) and a dual PI3Kδ/γ inhibitor (duvelisib) on the migration and proliferation of MCL cells. Results: We found that a distinctive feature of primary MCL cells is the elevated expression of PI3Kγ relative to that in other B-cell malignancies (Figure below). Our preliminary data provide compelling hints that high levels of PI3Kγ in MCL cells resident in tissues correlate with poor disease outcome. The functional role of PI3Kγ in MCL cells was differentiated from that of PI3Kδ: CZC24832 and duvelisib inhibited CCL21-induced migration of PI3Kγ-positive MAVER-1 and primary MCL cells but had no effect on PI3Kγ-negative JEKO-1 cells. Interestingly, duvelisib was more effective than CZC24832 in these assays, particularly with respect to migration of primary MCL cells. In contrast, specific inhibition of PI3Kδ with idelalisib did not affect CCL21-induced migration of the MCL cells used in this study, but did block BCR-induced signalling and its effects. These data suggest that when PI3Kγ is aberrantly expressed by MCL cells, these cells become reliant on this PI3K isoform for chemokine-induced migration and tissue residency. Thus, duvelisib may have a therapeutic advantage in MCL by restricting entry and retention of malignant cells within the mantle zone. Further functional analysis showed that inhibition of PI3Kγ with duvelisib and CZC24836 inhibited proliferation of MAVER-1 but not JEKO-1 cells, whereas specific inhibition of PI3Kδ had no effect on cell division in either cell type. Keywords: Duvelisib; mantle cell lymphoma (MCL); PI3K/AKT/mTOR. Disclosures: Till, K: Research Funding: Verastem Inc. Weaver, D: Employment Leadership Position: Verastem Oncology; Consultant Advisory Role: FemtoDx, Nanogen Therapeutics; Stock Ownership: Verastem Oncology, FemtoDx, Nanogen Therapeutics. Pachter, J: Employment Leadership Position: Verastem Oncology; Stock Ownership: Verastem Oncology. Pettitt, A: Research Funding: Verastem Oncology, Celgene, Chugai, Gilead, GSK/Novartis, Roche; Other Remuneration: Celgene, Gilead. Slupsky, J: Research Funding: Verastem Oncology." @default.
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• W2949384612 date "2019-06-01" @default.
• W2949384612 modified "2023-09-27" @default.
• W2949384612 title "POTENTIAL THERAPEUTIC ADVANTAGE FOR DUVELISIB IN MANTLE CELL LYMPHOMA: PI3Kδ AND OVEREXPRESSED PI3Kγ IN LYMPHOMA CELLS HAVE SPECIALIZED FUNCTIONAL ROLES" @default.
• W2949384612 doi "https://doi.org/10.1002/hon.194_2631" @default.
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