title: PI3Kδ and PI3Kγ isoforms have distinct functions in regulating pro-tumoural signalling in the multiple myeloma microenvironment.
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.
authors.affiliation: Department of Molecular Haematology, Norwich Medical School, The University of East Anglia, Norwich Research Park, Norwich, UK.
authors.forename: R E
authors.initials: RE
authors.lastname: Piddock
authors.affiliation: Department of Molecular Haematology, Norwich Medical School, The University of East Anglia, Norwich Research Park, Norwich, UK.
authors.forename: N
authors.initials: N
authors.lastname: Loughran
authors.affiliation: Department of Molecular Haematology, Norwich Medical School, The University of East Anglia, Norwich Research Park, Norwich, UK.
authors.forename: C R
authors.initials: CR
authors.lastname: Marlein
authors.affiliation: School of Biological Sciences, The University of East Anglia, Norwich Research Park, Norwich, UK.
authors.forename: S D
authors.initials: SD
authors.lastname: Robinson
authors.affiliation: Norwich Medical School, The University of East Anglia, Norwich Research Park, Norwich, UK.
authors.forename: D R
authors.initials: DR
authors.lastname: Edwards
authors.affiliation: Department of Molecular Haematology, Norwich Medical School, The University of East Anglia, Norwich Research Park, Norwich, UK.
authors.forename: S
authors.initials: S
authors.lastname: Yu
authors.affiliation: Department of Molecular Haematology, Norwich Medical School, The University of East Anglia, Norwich Research Park, Norwich, UK.
authors.forename: G E
authors.initials: GE
authors.lastname: Pillinger
authors.affiliation: Norwich Medical School, The University of East Anglia, Norwich Research Park, Norwich, UK.
authors.forename: Z
authors.initials: Z
authors.lastname: Zhou
authors.affiliation: Department of Molecular Haematology, Norwich Medical School, The University of East Anglia, Norwich Research Park, Norwich, UK.
authors.forename: L
authors.initials: L
authors.lastname: Zaitseva
authors.affiliation: Department of Haematology, Norfolk and Norwich University Hospitals NHS Trust, Colney Lane, Norwich, UK.
authors.forename: M J
authors.initials: MJ
authors.lastname: Auger
authors.affiliation: Department of Molecular Haematology, Norwich Medical School, The University of East Anglia, Norwich Research Park, Norwich, UK.
authors.forename: S A
authors.initials: SA
authors.lastname: Rushworth
authors.affiliation: Department of Molecular Haematology, Norwich Medical School, The University of East Anglia, Norwich Research Park, Norwich, UK.|Department of Haematology, Norfolk and Norwich University Hospitals NHS Trust, Colney Lane, Norwich, UK.
authors.forename: K M
authors.initials: KM
authors.lastname: Bowles
mesh_terms: D000818:Animals; D017209:Apoptosis; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D002470:Cell Survival / Q000235:genetics; D058534:Class I Phosphatidylinositol 3-Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D058544:Class Ib Phosphatidylinositol 3-Kinase / Q000378:metabolism*; D004195:Disease Models, Animal; D064593:Heterografts; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism / Q000494:pharmacology; D051379:Mice; D009101:Multiple Myeloma / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D020033:Protein Isoforms; D021122:Protein Subunits; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D059016:Tumor Microenvironment; D023041:Xenograft Model Antitumor Assays
chemical_list: D015850:Interleukin-6; D000081082:Phosphoinositide-3 Kinase Inhibitors; D020033:Protein Isoforms; D021122:Protein Subunits; D058534:Class I Phosphatidylinositol 3-Kinases; D058544:Class Ib Phosphatidylinositol 3-Kinase; C486018:PIK3CD protein, human; C546760:PIK3CG protein, human; D051057:Proto-Oncogene Proteins c-akt