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Piddock, R E, Loughran, N, Marlein, C R, Robinson, S D 
ORCID: https://orcid.org/0000-0002-6606-7588, Edwards, D R ORCID: https://orcid.org/0000-0002-3292-2064, Yu, S, Pillinger, G E, Zhou, Z, Zaitseva, L, Auger, M J, Rushworth, S A and Bowles, K M ORCID: https://orcid.org/0000-0003-1334-4526
(2017)
PI3Kδ and PI3Kγ isoforms have distinct functions in regulating pro-tumoural signalling in the multiple myeloma microenvironment.
Blood Cancer Journal, 7 (3).
ISSN 2044-5385
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Abstract
Phosphoinositide-3-kinase and protein kinase B (PI3K-AKT) is upregulated in multiple myeloma (MM). Using a combination of short hairpin RNA (shRNA) lentivirus-mediated knockdown and pharmacologic isoform-specific inhibition we investigated the role of the PI3K p110γ (PI3Kγ) subunit in regulating MM proliferation and bone marrow microenvironment-induced MM interactions. We compared this with inhibition of the PI3K p110δ (PI3kδ) subunit and with combined PI3kδ/γ dual inhibition. We found that MM cell adhesion and migration were PI3Kγ-specific functions, with PI3kδ inhibition having no effect in MM adhesion or migration assays. At concentration of the dual PI3Kδ/γ inhibitor duvelisib, which can be achieved in vivo we saw a decrease in AKT phosphorylation at s473 after tumour activation by bone marrow stromal cells (BMSC) and interleukin-6. Moreover, after drug treatment of BMSC/tumour co-culture activation assays only dual PI3kδ/γ inhibition was able to induce MM apoptosis. shRNA lentiviral-mediated targeting of either PI3Kδ or PI3Kγ alone, or both in combination, increased survival of NSG mice xeno-transplanted with MM cells. Moreover, treatment with duvelisib reduced MM tumour burden in vivo. We report that PI3Kδ and PI3Kγ isoforms have distinct functions in MM and that combined PI3kδ/γ isoform inhibition has anti-MM activity. Here we provide a scientific rationale for trials of dual PI3kδ/γ inhibition in patients with MM.
| Item Type: | Article |
|---|---|
| Faculty \ School: | Faculty of Medicine and Health Sciences > Norwich Medical School Faculty of Science > School of Biological Sciences |
| UEA Research Groups: | Faculty of Science > Research Groups > Cells and Tissues Faculty of Medicine and Health Sciences > Research Groups > Cancer Studies Faculty of Medicine and Health Sciences > Research Centres > Metabolic Health |
| Related URLs: | |
| Depositing User: | Pure Connector |
| Date Deposited: | 21 Mar 2017 01:41 |
| Last Modified: | 24 Oct 2023 00:48 |
| URI: | https://ueaeprints.uea.ac.uk/id/eprint/63022 |
| DOI: | 10.1038/bcj.2017.16 |
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