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  1. Article ; Online: Precision Targeting of Mutant PI3Kα.

    Gong, Grace Q / Vanhaesebroeck, Bart

    Cancer discovery

    2024  Volume 14, Issue 2, Page(s) 204–207

    Abstract: PIK3CA, which encodes the p110α catalytic subunit of PI 3-kinase alpha (PI3Kα), is one of the most frequently genetically activated kinases in solid tumors. In two back-to-back papers, Varkaris and colleagues report on the development of a novel ... ...

    Abstract PIK3CA, which encodes the p110α catalytic subunit of PI 3-kinase alpha (PI3Kα), is one of the most frequently genetically activated kinases in solid tumors. In two back-to-back papers, Varkaris and colleagues report on the development of a novel allosteric PI3Kα-mutant-selective inhibitor and early clinical experience with this compound. See related article by Varkaris et al., p. 227 (6) . See related article by Varkaris et al., p. 240 (5) .
    MeSH term(s) Humans ; Phosphatidylinositol 3-Kinases/genetics ; Mutation ; Phosphoinositide-3 Kinase Inhibitors ; Class I Phosphatidylinositol 3-Kinases/genetics ; Antineoplastic Agents/pharmacology ; Protein Kinase Inhibitors/pharmacology ; Protein Kinase Inhibitors/therapeutic use
    Chemical Substances Phosphatidylinositol 3-Kinases (EC 2.7.1.-) ; Phosphoinositide-3 Kinase Inhibitors ; Class I Phosphatidylinositol 3-Kinases (EC 2.7.1.137) ; Antineoplastic Agents ; Protein Kinase Inhibitors
    Language English
    Publishing date 2024-01-29
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2625242-9
    ISSN 2159-8290 ; 2159-8274
    ISSN (online) 2159-8290
    ISSN 2159-8274
    DOI 10.1158/2159-8290.CD-23-1392
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  2. Article ; Online: Precision Targeting of Mutant PI3Kα in Cancer by Selective Degradation.

    Vanhaesebroeck, Bart / Burke, John E / Madsen, Ralitsa R

    Cancer discovery

    2022  Volume 12, Issue 1, Page(s) 20–22

    Abstract: ... ...

    Abstract PIK3CA
    MeSH term(s) Class I Phosphatidylinositol 3-Kinases/genetics ; Humans ; Neoplasms/drug therapy ; Neoplasms/genetics ; Protein Kinase Inhibitors/pharmacology ; Protein Kinase Inhibitors/therapeutic use
    Chemical Substances Protein Kinase Inhibitors ; Class I Phosphatidylinositol 3-Kinases (EC 2.7.1.137)
    Language English
    Publishing date 2022-09-01
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Comment
    ZDB-ID 2625242-9
    ISSN 2159-8290 ; 2159-8274
    ISSN (online) 2159-8290
    ISSN 2159-8274
    DOI 10.1158/2159-8290.CD-21-1411
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  3. Article ; Online: Cracking the context-specific PI3K signaling code.

    Madsen, Ralitsa R / Vanhaesebroeck, Bart

    Science signaling

    2020  Volume 13, Issue 613

    Abstract: Specificity in signal transduction is determined by the ability of cells to "encode" and subsequently "decode" different environmental signals. Akin to computer software, this "signaling code" governs context-dependent execution of cellular programs ... ...

    Abstract Specificity in signal transduction is determined by the ability of cells to "encode" and subsequently "decode" different environmental signals. Akin to computer software, this "signaling code" governs context-dependent execution of cellular programs through modulation of signaling dynamics and can be corrupted by disease-causing mutations. Class IA phosphoinositide 3-kinase (PI3K) signaling is critical for normal growth and development and is dysregulated in human disorders such as benign overgrowth syndromes, cancer, primary immune deficiency, and metabolic syndrome. Despite decades of PI3K research, understanding of context-dependent regulation of the PI3K pathway and of the underlying signaling code remains rudimentary. Here, we review current knowledge on context-specific PI3K signaling and how technological advances now make it possible to move from a qualitative to quantitative understanding of this pathway. Insight into how cellular PI3K signaling is encoded or decoded may open new avenues for rational pharmacological targeting of PI3K-associated diseases. The principles of PI3K context-dependent signal encoding and decoding described here are likely applicable to most, if not all, major cell signaling pathways.
    MeSH term(s) Animals ; Humans ; Metabolic Syndrome/drug therapy ; Metabolic Syndrome/enzymology ; Metabolic Syndrome/genetics ; Metabolic Syndrome/pathology ; Neoplasm Proteins/antagonists & inhibitors ; Neoplasm Proteins/genetics ; Neoplasm Proteins/metabolism ; Neoplasms/drug therapy ; Neoplasms/enzymology ; Neoplasms/genetics ; Neoplasms/pathology ; Phosphatidylinositol 3-Kinase/genetics ; Phosphatidylinositol 3-Kinase/metabolism ; Phosphoinositide-3 Kinase Inhibitors/therapeutic use ; Primary Immunodeficiency Diseases/drug therapy ; Primary Immunodeficiency Diseases/enzymology ; Primary Immunodeficiency Diseases/genetics ; Primary Immunodeficiency Diseases/pathology ; Signal Transduction
    Chemical Substances Neoplasm Proteins ; Phosphoinositide-3 Kinase Inhibitors ; Phosphatidylinositol 3-Kinase (EC 2.7.1.137)
    Language English
    Publishing date 2020-01-07
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 2417226-1
    ISSN 1937-9145 ; 1945-0877
    ISSN (online) 1937-9145
    ISSN 1945-0877
    DOI 10.1126/scisignal.aay2940
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  4. Article ; Online: Phosphoinositide lipids in primary cilia biology.

    Conduit, Sarah E / Vanhaesebroeck, Bart

    The Biochemical journal

    2020  Volume 477, Issue 18, Page(s) 3541–3565

    Abstract: Primary cilia are solitary signalling organelles projecting from the surface of most cell types. Although the ciliary membrane is continuous with the plasma membrane it exhibits a unique phospholipid composition, a feature essential for normal cilia ... ...

    Abstract Primary cilia are solitary signalling organelles projecting from the surface of most cell types. Although the ciliary membrane is continuous with the plasma membrane it exhibits a unique phospholipid composition, a feature essential for normal cilia formation and function. Recent studies have illustrated that distinct phosphoinositide lipid species localise to specific cilia subdomains, and have begun to build a 'phosphoinositide map' of the cilium. The abundance and localisation of phosphoinositides are tightly regulated by the opposing actions of lipid kinases and lipid phosphatases that have also been recently discovered at cilia. The critical role of phosphoinositides in cilia biology is highlighted by the devastating consequences of genetic defects in cilia-associated phosphoinositide regulatory enzymes leading to ciliopathy phenotypes in humans and experimental mouse and zebrafish models. Here we provide a general introduction to primary cilia and the roles phosphoinositides play in cilia biology. In addition to increasing our understanding of fundamental cilia biology, this rapidly expanding field may inform novel approaches to treat ciliopathy syndromes caused by deregulated phosphoinositide metabolism.
    MeSH term(s) Animals ; Cell Membrane/genetics ; Cell Membrane/metabolism ; Cell Membrane/pathology ; Cilia/genetics ; Cilia/metabolism ; Cilia/pathology ; Ciliopathies/genetics ; Ciliopathies/metabolism ; Ciliopathies/pathology ; Humans ; Mice ; Phosphatidylinositols/genetics ; Phosphatidylinositols/metabolism ; Signal Transduction ; Zebrafish/genetics ; Zebrafish/metabolism
    Chemical Substances Phosphatidylinositols
    Language English
    Publishing date 2020-09-22
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 2969-5
    ISSN 1470-8728 ; 0006-2936 ; 0306-3275 ; 0264-6021
    ISSN (online) 1470-8728
    ISSN 0006-2936 ; 0306-3275 ; 0264-6021
    DOI 10.1042/BCJ20200277
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  5. Article ; Online: Sequential targeting of PI3Kδ and LAG3 as an effective anti-cancer approach.

    Lauder, Sarah N / Vanhaesebroeck, Bart / Gallimore, Awen

    British journal of cancer

    2021  Volume 125, Issue 4, Page(s) 467–469

    Abstract: Emerging studies have demonstrated the potential of PI3Kδ blockade as an immunotherapy for solid tumours. In pre-clinical models, we recently demonstrated that anti-LAG3 immune checkpoint blockade vastly potentiated PI3Kδ-based immunotherapy, enabling ... ...

    Abstract Emerging studies have demonstrated the potential of PI3Kδ blockade as an immunotherapy for solid tumours. In pre-clinical models, we recently demonstrated that anti-LAG3 immune checkpoint blockade vastly potentiated PI3Kδ-based immunotherapy, enabling successful tumour control in all treated mice.
    MeSH term(s) Animals ; Antigens, CD/immunology ; Class I Phosphatidylinositol 3-Kinases/immunology ; Drug Resistance, Neoplasm/drug effects ; Drug Synergism ; Humans ; Immune Checkpoint Inhibitors/pharmacology ; Immune Checkpoint Inhibitors/therapeutic use ; Immunotherapy ; Mice ; Neoplasms/drug therapy ; Neoplasms/immunology ; Tumor Microenvironment ; Xenograft Model Antitumor Assays ; Lymphocyte Activation Gene 3 Protein
    Chemical Substances Antigens, CD ; Immune Checkpoint Inhibitors ; Class I Phosphatidylinositol 3-Kinases (EC 2.7.1.137) ; PIK3CD protein, human (EC 2.7.1.137) ; Lymphocyte Activation Gene 3 Protein
    Language English
    Publishing date 2021-04-06
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 80075-2
    ISSN 1532-1827 ; 0007-0920
    ISSN (online) 1532-1827
    ISSN 0007-0920
    DOI 10.1038/s41416-021-01285-1
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  6. Article ; Online: Lessons for cancer drug treatment from tackling a non-cancerous overgrowth syndrome.

    Semple, Robert K / Vanhaesebroeck, Bart

    Nature

    2018  Volume 558, Issue 7711, Page(s) 523–525

    MeSH term(s) Antineoplastic Agents ; Class I Phosphatidylinositol 3-Kinases ; Humans ; Neoplasms ; Phosphatidylinositol 3-Kinases ; Syndrome
    Chemical Substances Antineoplastic Agents ; Phosphatidylinositol 3-Kinases (EC 2.7.1.-) ; Class I Phosphatidylinositol 3-Kinases (EC 2.7.1.137) ; PIK3CA protein, human (EC 2.7.1.137)
    Language English
    Publishing date 2018-06-25
    Publishing country England
    Document type News ; Comment
    ZDB-ID 120714-3
    ISSN 1476-4687 ; 0028-0836
    ISSN (online) 1476-4687
    ISSN 0028-0836
    DOI 10.1038/d41586-018-05365-w
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  7. Article ; Online: Inactivating the lipid kinase activity of PI3KC2β is sufficient to rescue myotubular myopathy in mice.

    Massana-Muñoz, Xènia / Goret, Marie / Nattarayan, Vasugi / Reiss, David / Kretz, Christine / Chicanne, Gaetan / Payrastre, Bernard / Vanhaesebroeck, Bart / Laporte, Jocelyn

    JCI insight

    2023  Volume 8, Issue 9

    Abstract: Phosphoinositides (PIs) are membrane lipids that regulate signal transduction and vesicular trafficking. X-linked centronuclear myopathy (XLCNM), also called myotubular myopathy, results from loss-of-function mutations in the MTM1 gene, which encodes the ...

    Abstract Phosphoinositides (PIs) are membrane lipids that regulate signal transduction and vesicular trafficking. X-linked centronuclear myopathy (XLCNM), also called myotubular myopathy, results from loss-of-function mutations in the MTM1 gene, which encodes the myotubularin phosphatidylinositol 3-phosphate (PtdIns3P) lipid phosphatase. No therapy for this disease is currently available. Previous studies showed that loss of expression of the class II phosphoinositide 3-kinase (PI3K) PI3KC2β (PI3KC2B) protein improved the phenotypes of an XLCNM mouse model. PI3Ks are well known to have extensive scaffolding functions and the importance of the catalytic activity of this PI3K for rescue remains unclear. Here, using PI3KC2β kinase-dead mice, we show that the selective inactivation of PI3KC2β kinase activity is sufficient to fully prevent muscle atrophy and weakness, histopathology, and sarcomere and triad disorganization in Mtm1-knockout mice. This rescue correlates with normalization of PtdIns3P level and mTORC1 activity, a key regulator of protein synthesis and autophagy. Conversely, lack of PI3KC2β kinase activity did not rescue the histopathology of the BIN1 autosomal CNM mouse model. Overall, these findings support the development of specific PI3KC2β kinase inhibitors to cure myotubular myopathy.
    MeSH term(s) Animals ; Mice ; Phosphatidylinositol 3-Kinases/genetics ; Phosphatidylinositols ; Mutation ; Mice, Knockout ; Myopathies, Structural, Congenital/genetics ; Myopathies, Structural, Congenital/pathology
    Chemical Substances Phosphatidylinositol 3-Kinases (EC 2.7.1.-) ; Phosphatidylinositols
    Language English
    Publishing date 2023-05-08
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ISSN 2379-3708
    ISSN (online) 2379-3708
    DOI 10.1172/jci.insight.151933
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  8. Article ; Online: PI3K isoforms in cell signalling and vesicle trafficking.

    Bilanges, Benoit / Posor, York / Vanhaesebroeck, Bart

    Nature reviews. Molecular cell biology

    2019  Volume 20, Issue 9, Page(s) 515–534

    Abstract: PI3Ks are a family of lipid kinases that phosphorylate intracellular inositol lipids to regulate signalling and intracellular vesicular traffic. Mammals have eight isoforms of PI3K, divided into three classes. The class I PI3Ks generate 3- ... ...

    Abstract PI3Ks are a family of lipid kinases that phosphorylate intracellular inositol lipids to regulate signalling and intracellular vesicular traffic. Mammals have eight isoforms of PI3K, divided into three classes. The class I PI3Ks generate 3-phosphoinositide lipids, which directly activate signal transduction pathways. In addition to being frequently genetically activated in cancer, similar mutations in class I PI3Ks have now also been found in a human non-malignant overgrowth syndrome and a primary immune disorder that predisposes to lymphoma. The class II and class III PI3Ks are regulators of membrane traffic along the endocytic route, in endosomal recycling and autophagy, with an often indirect effect on cell signalling. Here, we summarize current knowledge of the different PI3K classes and isoforms, focusing on recently uncovered biological functions and the mechanisms by which these kinases are activated. Deeper insight into the PI3K isoforms will undoubtedly continue to contribute to a better understanding of fundamental cell biological processes and, ultimately, of human disease.
    MeSH term(s) Animals ; Biological Transport, Active ; Endocytosis ; Endosomes/metabolism ; Humans ; Isoenzymes/metabolism ; Lymphoma/enzymology ; Lymphoma/pathology ; Neoplasm Proteins/metabolism ; Phosphatidylinositol 3-Kinases/metabolism ; Signal Transduction
    Chemical Substances Isoenzymes ; Neoplasm Proteins
    Language English
    Publishing date 2019-06-04
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 2031313-5
    ISSN 1471-0080 ; 1471-0072
    ISSN (online) 1471-0080
    ISSN 1471-0072
    DOI 10.1038/s41580-019-0129-z
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    Zs.A 5446: Show issues Location:
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  9. Article ; Online: Author Correction: PI3K inhibitors are finally coming of age.

    Vanhaesebroeck, Bart / Perry, Matthew W D / Brown, Jennifer R / André, Fabrice / Okkenhaug, Klaus

    Nature reviews. Drug discovery

    2021  Volume 20, Issue 10, Page(s) 798

    Language English
    Publishing date 2021-09-02
    Publishing country England
    Document type Published Erratum
    ZDB-ID 2062954-0
    ISSN 1474-1784 ; 1474-1776
    ISSN (online) 1474-1784
    ISSN 1474-1776
    DOI 10.1038/s41573-021-00300-7
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  10. Article ; Online: PI3K inhibitors are finally coming of age.

    Vanhaesebroeck, Bart / Perry, Matthew W D / Brown, Jennifer R / André, Fabrice / Okkenhaug, Klaus

    Nature reviews. Drug discovery

    2021  Volume 20, Issue 10, Page(s) 741–769

    Abstract: Overactive phosphoinositide 3-kinase (PI3K) in cancer and immune dysregulation has spurred extensive efforts to develop therapeutic PI3K inhibitors. Although progress has been hampered by issues such as poor drug tolerance and drug resistance, several ... ...

    Abstract Overactive phosphoinositide 3-kinase (PI3K) in cancer and immune dysregulation has spurred extensive efforts to develop therapeutic PI3K inhibitors. Although progress has been hampered by issues such as poor drug tolerance and drug resistance, several PI3K inhibitors have now received regulatory approval - the PI3Kα isoform-selective inhibitor alpelisib for the treatment of breast cancer and inhibitors mainly aimed at the leukocyte-enriched PI3Kδ in B cell malignancies. In addition to targeting cancer cell-intrinsic PI3K activity, emerging evidence highlights the potential of PI3K inhibitors in cancer immunotherapy. This Review summarizes key discoveries that aid the clinical translation of PI3Kα and PI3Kδ inhibitors, highlighting lessons learnt and future opportunities.
    MeSH term(s) Animals ; Humans ; Immune System Diseases/drug therapy ; Immune System Diseases/genetics ; Immunotherapy ; Neoplasms/drug therapy ; Neoplasms/genetics ; Phosphatidylinositol 3-Kinases/drug effects ; Phosphatidylinositol 3-Kinases/metabolism ; Phosphoinositide-3 Kinase Inhibitors/pharmacology ; Phosphoinositide-3 Kinase Inhibitors/therapeutic use
    Chemical Substances Phosphoinositide-3 Kinase Inhibitors
    Language English
    Publishing date 2021-06-14
    Publishing country England
    Document type Journal Article ; Review
    ZDB-ID 2062954-0
    ISSN 1474-1784 ; 1474-1776
    ISSN (online) 1474-1784
    ISSN 1474-1776
    DOI 10.1038/s41573-021-00209-1
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