PI3Kδ and PI3Kγ isoforms have distinct functions in regulating pro-tumoural signalling in the multiple myeloma microenvironment

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.

• Publication year

  2017

• Venue

  Blood Cancer Journal

• Publication date

  2017-03-01

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1038/bcj.2017.16PMID 28282033PMCID 5380901
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Preliminary safety, pharmacokinetics, and pharmacodynamics of duvelisib plus rituximab or obinutuzumab in patients with previously untreated CD20+ follicular lymphoma.

  2016cited by this paper
• The phosphoinositide-3-kinase (PI3K)-delta and gamma inhibitor, IPI-145 (Duvelisib), overcomes signals from the PI3K/AKT/S6 pathway and promotes apoptosis in CLL

  2015cited by this paper
• Adjuvant Therapy Reduces Rate of Dissemination but Shortens Survival Thereafter.

  2015cited by this paper
• An Advanced Preclinical Mouse Model for Acute Myeloid Leukemia Using Patients' Cells of Various Genetic Subgroups and In Vivo Bioluminescence Imaging

  2015cited by this paper
• How I treat relapsed myeloma.

  2015cited by this paper
• Cancer statistics, 2014

  2014cited by this paper
• A potential therapeutic strategy for chronic lymphocytic leukemia by combining Idelalisib and GS-9973, a novel spleen tyrosine kinase (Syk) inhibitor

  2014cited by this paper
• Idelalisib and rituximab in relapsed chronic lymphocytic leukemia.

  2014cited by this paper
• Idelalisib, an inhibitor of phosphatidylinositol 3-kinase p110δ, for relapsed/refractory chronic lymphocytic leukemia.

  2014cited by this paper
• Identification of Bruton's tyrosine kinase as a therapeutic target in acute myeloid leukemia.

  2014cited by this paper
• p110δ PI3 kinase pathway: emerging roles in cancer

  2012cited by this paper
• G Protein–Coupled Receptor–Mediated Activation of p110β by Gβγ Is Required for Cellular Transformation and Invasiveness

  2012cited by this paper
• Characterization of the Mechanism of Action of the Pan Class I PI3K Inhibitor NVP-BKM120 across a Broad Range of Concentrations

  2012cited by this paper
• The high Nrf2 expression in human acute myeloid leukemia is driven by NF-κB and underlies its chemo-resistance.

  2012cited by this paper
• mTOR signaling in growth control and disease.

  2012cited by this paper
• CAL-101, a p110delta selective phosphatidylinositol-3-kinase inhibitor for the treatment of B-cell malignancies, inhibits PI3K signaling and cellular viability.

  2011cited by this paper
• Balanced Interactions between Lyn, the p85α Regulatory Subunit of Class IA Phosphatidylinositol-3-Kinase, and SHIP Are Essential for Mast Cell Growth and Maturation

  2011cited by this paper
• PI3K as a target for therapy in haematological malignancies.

  2010cited by this paper
• Phosphatidylinositol 3-kinase- inhibitor CAL-101 shows promising preclinical activity in chronic lymphocytic leukemia by antagonizing intrinsic and extrinsic cellular survival signals

  2010cited by this paper
• Adhesion molecules--The lifelines of multiple myeloma cells.

  2010cited by this paper
• PI3K/p110{delta} is a novel therapeutic target in multiple myeloma.

  2010cited by this paper
• PI3K/p110 (cid:1) is a novel therapeutic target in multiple myeloma

  2010cited by this paper
• High frequency of PTEN, PI3K, and AKT abnormalities in T-cell acute lymphoblastic leukemia.

  2009cited by this paper
• Beta1 integrin adhesion enhances IL-6-mediated STAT3 signaling in myeloma cells: implications for microenvironment influence on tumor survival and proliferation.

  2009cited by this paper
• Targeting survival cascades induced by activation of Ras/Raf/MEK/ERK, PI3K/PTEN/Akt/mTOR and Jak/STAT pathways for effective leukemia therapy

  2008cited by this paper
• PI3K pathway regulates survival of cancer stem cells residing in the perivascular niche following radiation in medulloblastoma in vivo.

  2008cited by this paper
• Tipifarnib and Bortezomib Are Synergistic and Overcome Cell Adhesion–Mediated Drug Resistance in Multiple Myeloma and Acute Myeloid Leukemia

  2006cited by this paper
• Role of B-cell-activating factor in adhesion and growth of human multiple myeloma cells in the bone marrow microenvironment.

  2006cited by this paper
• Exploration of genetic alterations in human endometrial cancer and melanoma: distinct tumorigenic pathways that share a frequent abnormal PI3K/AKT cascade.

  2005cited by this paper
• A novel orally active proteasome inhibitor induces apoptosis in multiple myeloma cells with mechanisms distinct from Bortezomib.

  2005cited by this paper
• The AKT kinase is activated in multiple myeloma tumor cells.

  2001cited by this paper
• Biologic sequelae of interleukin-6 induced PI3-K/Akt signaling in multiple myeloma

  2001cited by this paper
• The proteasome inhibitor PS-341 inhibits growth, induces apoptosis, and overcomes drug resistance in human multiple myeloma cells.

  2001cited by this paper
• Function of PI3Kgamma in thymocyte development, T cell activation, and neutrophil migration.

  2000cited by this paper
• Role of IKK1 and IKK2 in Lipopolysaccharide Signaling in Human Monocytic Cells*

  1998cited by this paper
• A Function for Phosphatidylinositol 3-Kinase β (p85α-p110β) in Fibroblasts during Mitogenesis: Requirement for Insulin- and Lysophosphatidic Acid-Mediated Signal Transduction

  1998cited by this paper
• A function for phosphatidylinositol 3-kinase beta (p85alpha-p110beta) in fibroblasts during mitogenesis: requirement for insulin- and lysophosphatidic acid-mediated signal transduction.

  1998cited by this paper
• Multiple myeloma cell adhesion-induced interleukin-6 expression in bone marrow stromal cells involves activation of NF-kappa B.

  1996cited by this paper
• Interleukin-6 in human multiple myeloma.

  1995cited by this paper
• Interleukin-6 prevents dexamethasone-induced myeloma cell death.

  1994cited by this paper
• Cancer statistics

  1989cited by this paper

• Quercetin alleviates imatinib-induced premature ovarian insufficiency by regulating mitophagy via the ROS/JNK/c-JUN pathway.

  2026cites this paper
• Targeting JAK/STAT axis in solid tumors: resolving the therapeutic paradox through upstream suppression and downstream disruption

  2026cites this paper
• Danshenol B alleviates central post-stroke pain by regulating the PIK3CG/NLRP3 signaling pathway

  2025cites this paper
• Exploring TGF-β Signaling in Cancer Progression: Prospects and Therapeutic Strategies

  2025cites this paper
• Revitalizing premature ovarian failure: quercetin counteracts imatinib-induced apoptosis via the PI3K/AKT signaling pathway based on network pharmacology

  2024cites this paper
• Harnessing the targeting potential of hyaluronic acid for augmented anticancer activity and safety of duvelisib-loaded nanoparticles in hematological malignancies.

  2024cites this paper
• Targeting the PI3K/AKT signaling pathway in anticancer research: a recent update on inhibitor design and clinical trials (2020–2023)

  2024cites this paper
• Therapeutic potential of anti-PIK3CG treatment for multiple myeloma via inhibiting c-Myc pathway

  2023cites this paper
• Discovery of Pyrazolo[1,5-a]pyrimidine derivative as a potent and selective PI3Kγ/δ dual inhibitor.

  2023cites this paper
• Transforming Growth Factor-Beta (TGF-β) Signaling in Cancer-A Betrayal Within

  2022cites this paper
• Pathogenic signaling in multiple myeloma.

  2022cites this paper
• Dual targeting of PI3K and BCL‐2 overcomes ibrutinib resistance in aggressive mantle cell lymphoma

  2022cites this paper
• PIK-75 overcomes venetoclax resistance via blocking PI3K-AKT signaling and MCL-1 expression in mantle cell lymphoma.

  2022cites this paper
• High expression of the phosphoinositide 3-kinase p11γ isoform can predict poor prognosis of non-small cell lung cancer.

  2022cites this paper
• Tissue-specific identification of multi-omics features for pan-cancer drug response prediction

  2022cites this paper
• Allosteric Site on SHIP2 Identified Through Fluorescent Ligand Screening and Crystallography: A Potential New Target for Intervention

  2021cites this paper
• CD38-Driven Mitochondrial Trafficking Promotes Bioenergetic Plasticity in Multiple Myeloma.

  2019cites this paper
• Combination trial of duvelisib (IPI‐145) with rituximab or bendamustine/rituximab in patients with non‐Hodgkin lymphoma or chronic lymphocytic leukemia

  2019cites this paper
• Integrative Network Analysis of Differentially Methylated and Expressed Genes for Biomarker Identification in Leukemia

  2019cites this paper
• Inhibition of PI3Kγ by AS605240 Protects tMCAO Mice by Attenuating pro-Inflammatory Signaling and Cytokine Release in Reactive Astrocytes.

  2019cites this paper
• The WNT receptor ROR2 drives the interaction of multiple myeloma cells with the microenvironment through AKT activation

  2019cites this paper
• Discovery, Optimization, and Evaluation of Potent and Highly Selective PI3Kγ-PI3Kδ Dual Inhibitors.

  2019cites this paper
• Next Generation Immunotherapy for Pancreatic Cancer: DNA Vaccination is Seeking New Combo Partners

  2018cites this paper
• Up-Regulation of PI 3-Kinases and the Activation of PI3K-Akt Signaling Pathway in Cancer Stem-Like Cells Through DNA Hypomethylation Mediated by the Cancer Microenvironment

  2018cites this paper
• NADPH oxidase-2 derived superoxide drives mitochondrial transfer from bone marrow stromal cells to leukemic blasts.

  2017cites this paper
• Questioning the role of selected somatic PIK3C2B mutations in squamous non-small cell lung cancer oncogenesis

  2017cites this paper
• The Role of PI3K Isoforms in Regulating Bone Marrow Microenvironment Signaling Focusing on Acute Myeloid Leukemia and Multiple Myeloma

  2017cites this paper