Roles of PI3Kγ and PI3Kδ in mantle cell lymphoma proliferation and migration contributing to efficacy of the PI3Kγ/δ inhibitor duvelisib.

Till, Kathleen J ORCID: 0000-0002-3172-5771, Abdullah, Mariah, Alnassfan, Tahera, Janet, Gallardo Zapata, Marks, Thomas, Coma, Silvia, Weaver, David T, Pachter, Jonathan A, Pettitt, Andrew R and Slupsky, Joseph R ORCID: 0000-0002-7410-9004 (2023) Roles of PI3Kγ and PI3Kδ in mantle cell lymphoma proliferation and migration contributing to efficacy of the PI3Kγ/δ inhibitor duvelisib. Scientific reports, 13 (1). 3793-.

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Official URL: http://dx.doi.org/10.1038/s41598-023-30148-3

Abstract

Mantle cell lymphoma (MCL) is an aggressive B-cell non-Hodgkin lymphoma that is incurable with existing therapies, and therefore presents a significant unmet clinical need. The ability of this disease to overcome therapy, including those that target the B cell receptor pathway which has a pathogenic role in MCL, highlights the need to develop new treatment strategies. Herein, we demonstrate that a distinguishing feature of lymph node resident MCL cells is the expression of phosphatidylinositol 3-kinase γ (PI3Kγ), a PI3K isoform that is not highly expressed in other B cells or B-cell malignancies. By exploring the role of PI3K in MCL using different PI3K isoform inhibitors, we provide evidence that duvelisib, a dual PI3Kδ/γ inhibitor, has a greater effect than PI3Kδ- and PI3Kγ-selective inhibitors in blocking the proliferation of primary MCL cells and MCL cell lines, and in inhibiting tumour growth in a mouse xenograft model. In addition, we demonstrated that PI3Kδ/γ signalling is critical for migration of primary MCL cells and cell lines. Our data indicates that aberrant expression of PI3Kγ is a critical feature of MCL pathogenesis. Thus, we suggest that the dual PI3Kδ/γ duvelisib would be effective for the treatment of mantle cell lymphoma.

Item Type:	Article
Uncontrolled Keywords:	Animals, Humans, Mice, Lymphoma, Mantle-Cell, Disease Models, Animal, Cell Proliferation, Phosphatidylinositol 3-Kinases, Phosphoinositide-3 Kinase Inhibitors
Divisions:	Faculty of Health and Life Sciences Faculty of Health and Life Sciences > Institute of Systems, Molecular and Integrative Biology
Depositing User:	Symplectic Admin
Date Deposited:	05 Apr 2023 09:00
Last Modified:	05 Apr 2023 09:00
DOI:	10.1038/s41598-023-30148-3
Open Access URL:	https://doi.org/10.1038/s41598-023-30148-3
Related URLs:	Author Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/3169464