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PMID: 28802037 Published · ppublish English Journal Article Review

The PI3K Pathway in Human Disease.

Cell ·Vol. 170 ·No. 4 ·2017-08-10 ·Pages 605-635

Fruman DA, Chiu H, Hopkins BD, Bagrodia S, Cantley LC, Abraham RT

Abstract

Phosphoinositide 3-kinase (PI3K) activity is stimulated by diverse oncogenes and growth factor receptors, and elevated PI3K signaling is considered a hallmark of cancer. Many PI3K pathway-targeted therapies have been tested in oncology trials, resulting in regulatory approval of one isoform-selective inhibitor (idelalisib) for treatment of certain blood cancers and a variety of other agents at different stages of development. In parallel to PI3K research by cancer biologists, investigations in other fields have uncovered exciting and often unpredicted roles for PI3K catalytic and regulatory subunits in normal cell function and in disease. Many of these functions impinge upon oncology by influencing the efficacy and toxicity of PI3K-targeted therapies. Here we provide a perspective on the roles of class I PI3Ks in the regulation of cellular metabolism and in immune system functions, two topics closely intertwined with cancer biology. We also discuss recent progress developing PI3K-targeted therapies for treatment of cancer and other diseases.

MeSH Terms
Animals Cell Physiological Phenomena Humans Immune System/metabolism Neoplasms/drug therapy,metabolism,pathology Phosphatidylinositol 3-Kinases/metabolism Signal Transduction
Chemicals
Phosphatidylinositol 3-Kinases
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Fruman David A
Department of Molecular Biology & Biochemistry, University of California, Irvine, Irvine, CA 92697-3900, USA. Electronic address: [email protected].
Chiu Honyin
Department of Molecular Biology & Biochemistry, University of California, Irvine, Irvine, CA 92697-3900, USA.
Hopkins Benjamin D
Meyer Cancer Center, Weill Cornell Medical College, 413 E. 69(th) Street, New York, NY 10021, USA.
Bagrodia Shubha
Oncology R&D Group, Pfizer Worldwide Research and Development, 10646/CB4 Science Center Drive, San Diego, CA 92121, USA.
Cantley Lewis C
Meyer Cancer Center, Weill Cornell Medical College, 413 E. 69(th) Street, New York, NY 10021, USA.
Abraham Robert T
Oncology R&D Group, Pfizer Worldwide Research and Development, 10646/CB4 Science Center Drive, San Diego, CA 92121, USA.
References (284)
284 references, click to expand
  1. Tumour-specific PI3K inhibition via nanoparticle-targeted delivery in head and neck squamous cell carcinoma.
    Nat Commun. 2017 Feb 13;8:14292 PMID: 28194032
  2. mTOR treatment in lymphangioleiomyomatosis: the role of everolimus.
    Expert Rev Respir Med. 2016;10 (3):249-60 PMID: 26847859
  3. The associations between Parkinson's disease and cancer: the plot thickens.
    Transl Neurodegener. 2015 Oct 26;4:20 PMID: 26504519
  4. Resistance to BET Bromodomain Inhibitors Is Mediated by Kinome Reprogramming in Ovarian Cancer.
    Cell Rep. 2016 Aug 2;16(5):1273-1286 PMID: 27452461
  5. Long-term p110α PI3K inactivation exerts a beneficial effect on metabolism.
    EMBO Mol Med. 2013 Apr;5(4):563-71 PMID: 23483710
  6. Phase I dose escalation study of the PI3kinase pathway inhibitor BKM120 and the oral poly (ADP ribose) polymerase (PARP) inhibitor olaparib for the treatment of high-grade serous ovarian and breast cancer.
    Ann Oncol. 2017 Mar 1;28(3):512-518 PMID: 27993796
  7. Randomized Open-Label Phase II Trial of Apitolisib (GDC-0980), a Novel Inhibitor of the PI3K/Mammalian Target of Rapamycin Pathway, Versus Everolimus in Patients With Metastatic Renal Cell Carcinoma.
    J Clin Oncol. 2016 May 10;34(14 ):1660-8 PMID: 26951309
  8. Role of the phosphoinositide 3-kinase p110delta in generation of type 2 cytokine responses and allergic airway inflammation.
    Eur J Immunol. 2007 Feb;37(2):416-24 PMID: 17236236
  9. Phosphoinositide 3-Kinase Regulates Glycolysis through Mobilization of Aldolase from the Actin Cytoskeleton.
    Cell. 2016 Jan 28;164(3):433-46 PMID: 26824656
  10. Somatic mosaic activating mutations in PIK3CA cause CLOVES syndrome.
    Am J Hum Genet. 2012 Jun 8;90(6):1108-15 PMID: 22658544
  11. The emerging mechanisms of isoform-specific PI3K signalling.
    Nat Rev Mol Cell Biol. 2010 May;11(5):329-41 PMID: 20379207
  12. Oncogenic mutations mimic and enhance dynamic events in the natural activation of phosphoinositide 3-kinase p110α (PIK3CA).
    Proc Natl Acad Sci U S A. 2012 Sep 18;109(38):15259-64 PMID: 22949682
  13. Isoform-specific phosphoinositide 3-kinase inhibitors exert distinct effects in solid tumors.
    Cancer Res. 2010 Feb 1;70(3):1164-72 PMID: 20103642
  14. PtdIns(3,4,5)P3-Dependent Activation of the mTORC2 Kinase Complex.
    Cancer Discov. 2015 Nov;5(11):1194-209 PMID: 26293922
  15. Targets for cell cycle arrest by the immunosuppressant rapamycin in yeast.
    Science. 1991 Aug 23;253(5022):905-9 PMID: 1715094
  16. Metabolic Reprogramming by the PI3K-Akt-mTOR Pathway in Cancer.
    Recent Results Cancer Res. 2016;207 :39-72 PMID: 27557534
  17. Systematic Functional Characterization of Resistance to PI3K Inhibition in Breast Cancer.
    Cancer Discov. 2016 Oct;6(10 ):1134-1147 PMID: 27604488
  18. Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer.
    N Engl J Med. 2012 Feb 9;366(6):520-9 PMID: 22149876
  19. Subclonal diversification of primary breast cancer revealed by multiregion sequencing.
    Nat Med. 2015 Jul;21(7):751-9 PMID: 26099045
  20. The CDK4/6 inhibitor LY2835219 has potent activity in combination with mTOR inhibitor in head and neck squamous cell carcinoma.
    Oncotarget. 2016 Mar 22;7(12):14803-13 PMID: 26909611
  21. Combination of antibody that inhibits ligand-independent HER3 dimerization and a p110α inhibitor potently blocks PI3K signaling and growth of HER2+ breast cancers.
    Cancer Res. 2013 Oct 1;73(19):6013-23 PMID: 23918797
  22. Cutting edge: the phosphoinositide 3-kinase p110 delta is critical for the function of CD4+CD25+Foxp3+ regulatory T cells.
    J Immunol. 2006 Nov 15;177(10):6598-602 PMID: 17082571
  23. Protein kinase B controls transcriptional programs that direct cytotoxic T cell fate but is dispensable for T cell metabolism.
    Immunity. 2011 Feb 25;34(2):224-36 PMID: 21295499
  24. SREBP activity is regulated by mTORC1 and contributes to Akt-dependent cell growth.
    Cell Metab. 2008 Sep;8(3):224-36 PMID: 18762023
  25. Synergy in activating class I PI3Ks.
    Trends Biochem Sci. 2015 Feb;40(2):88-100 PMID: 25573003
  26. IL-10 Potentiates Differentiation of Human Induced Regulatory T Cells via STAT3 and Foxo1.
    J Immunol. 2015 Oct 15;195(8):3665-74 PMID: 26363058
  27. Specificity in recognition of phosphopeptides by src-homology 2 domains.
    J Cell Sci Suppl. 1994;18:121-6 PMID: 7533766
  28. PI3K isoform dependence of PTEN-deficient tumors can be altered by the genetic context.
    Proc Natl Acad Sci U S A. 2014 Apr 29;111(17 ):6395-400 PMID: 24737887
  29. Phosphoproteomic comparison of Pik3ca and Pten signalling identifies the nucleotidase NT5C as a novel AKT substrate.
    Sci Rep. 2017 Jan 06;7:39985 PMID: 28059163
  30. Phase I Dose-Escalation Study of Taselisib, an Oral PI3K Inhibitor, in Patients with Advanced Solid Tumors.
    Cancer Discov. 2017 Jul;7(7):704-715 PMID: 28331003
  31. SHORT syndrome with partial lipodystrophy due to impaired phosphatidylinositol 3 kinase signaling.
    Am J Hum Genet. 2013 Jul 11;93(1):150-7 PMID: 23810379
  32. Resistance to everolimus driven by epigenetic regulation of MYC in ER+ breast cancers.
    Oncotarget. 2015 Feb 10;6(4):2407-20 PMID: 25537515
  33. The intricate regulation and complex functions of the Class III phosphoinositide 3-kinase Vps34.
    Biochem J. 2016 Aug 1;473(15):2251-71 PMID: 27470591
  34. Effects of MAPK and PI3K pathways on PD-L1 expression in melanoma.
    Clin Cancer Res. 2014 Jul 1;20(13):3446-57 PMID: 24812408
  35. PI3Kδ inhibition by idelalisib in patients with relapsed indolent lymphoma.
    N Engl J Med. 2014 Mar 13;370(11):1008-18 PMID: 24450858
  36. Emerging evidence of signalling roles for PI(3,4)P2 in Class I and II PI3K-regulated pathways.
    Biochem Soc Trans. 2016 Feb;44(1):307-14 PMID: 26862220
  37. Idelalisib or placebo in combination with bendamustine and rituximab in patients with relapsed or refractory chronic lymphocytic leukaemia: interim results from a phase 3, randomised, double-blind, placebo-controlled trial.
    Lancet Oncol. 2017 Mar;18(3):297-311 PMID: 28139405
  38. PI3K p110delta regulates T-cell cytokine production during primary and secondary immune responses in mice and humans.
    Blood. 2010 Mar 18;115(11):2203-13 PMID: 20081091
  39. Phosphoinositide 3-kinase: diverse roles in immune cell activation.
    Annu Rev Immunol. 2004;22:563-98 PMID: 15032589
  40. Receptor tyrosine kinases and TLR/IL1Rs unexpectedly activate myeloid cell PI3kγ, a single convergent point promoting tumor inflammation and progression.
    Cancer Cell. 2011 Jun 14;19(6):715-27 PMID: 21665146
  41. Phosphoproteomic analysis identifies Grb10 as an mTORC1 substrate that negatively regulates insulin signaling.
    Science. 2011 Jun 10;332(6035):1322-6 PMID: 21659605
  42. Regulation of mTORC1 by PI3K signaling.
    Trends Cell Biol. 2015 Sep;25(9):545-55 PMID: 26159692
  43. Agammaglobulinemia and absent B lineage cells in a patient lacking the p85α subunit of PI3K.
    J Exp Med. 2012 Mar 12;209(3):463-70 PMID: 22351933
  44. Cytokine stimulation promotes glucose uptake via phosphatidylinositol-3 kinase/Akt regulation of Glut1 activity and trafficking.
    Mol Biol Cell. 2007 Apr;18(4):1437-46 PMID: 17301289
  45. Early Adaptation and Acquired Resistance to CDK4/6 Inhibition in Estrogen Receptor-Positive Breast Cancer.
    Cancer Res. 2016 Apr 15;76(8):2301-13 PMID: 27020857
  46. Regulation and function of mTOR signalling in T cell fate decisions.
    Nat Rev Immunol. 2012 Apr 20;12(5):325-38 PMID: 22517423
  47. Signaling by the phosphoinositide 3-kinase family in immune cells.
    Annu Rev Immunol. 2013;31:675-704 PMID: 23330955
  48. A Phase Ib Study of BEZ235, a Dual Inhibitor of Phosphatidylinositol 3-Kinase (PI3K) and Mammalian Target of Rapamycin (mTOR), in Patients With Advanced Renal Cell Carcinoma.
    Oncologist. 2016 Jul;21(7):787-8 PMID: 27286790
  49. Asymmetric inheritance of mTORC1 kinase activity during division dictates CD8(+) T cell differentiation.
    Nat Immunol. 2016 Jun;17 (6):704-11 PMID: 27064374
  50. Ablation of PI3K blocks BCR-ABL leukemogenesis in mice, and a dual PI3K/mTOR inhibitor prevents expansion of human BCR-ABL+ leukemia cells.
    J Clin Invest. 2008 Sep;118(9):3038-50 PMID: 18704194
  51. P-Rex1, a PtdIns(3,4,5)P3- and Gbetagamma-regulated guanine-nucleotide exchange factor for Rac.
    Cell. 2002 Mar 22;108(6):809-21 PMID: 11955434
  52. Loss of PTEN Promotes Resistance to T Cell-Mediated Immunotherapy.
    Cancer Discov. 2016 Feb;6(2):202-16 PMID: 26645196
  53. MYC on the path to cancer.
    Cell. 2012 Mar 30;149(1):22-35 PMID: 22464321
  54. Germinal centre hypoxia and regulation of antibody qualities by a hypoxia response system.
    Nature. 2016 Sep 8;537(7619):234-238 PMID: 27501247
  55. Foxo1 regulates marginal zone B-cell development.
    Eur J Immunol. 2010 Jul;40(7):1890-6 PMID: 20449867
  56. Foxo1 links homing and survival of naive T cells by regulating L-selectin, CCR7 and interleukin 7 receptor.
    Nat Immunol. 2009 Feb;10 (2):176-84 PMID: 19136962
  57. PIK3CA mutation H1047R is associated with response to PI3K/AKT/mTOR signaling pathway inhibitors in early-phase clinical trials.
    Cancer Res. 2013 Jan 1;73(1):276-84 PMID: 23066039
  58. Antitumor efficacy of PKI-587, a highly potent dual PI3K/mTOR kinase inhibitor.
    Clin Cancer Res. 2011 May 15;17(10):3193-203 PMID: 21325073
  59. PI3K signalling in inflammation.
    Biochim Biophys Acta. 2015 Jun;1851(6):882-97 PMID: 25514767
  60. CDK 4/6 inhibitors sensitize PIK3CA mutant breast cancer to PI3K inhibitors.
    Cancer Cell. 2014 Jul 14;26(1):136-49 PMID: 25002028
  61. Measurement of PIP3 levels reveals an unexpected role for p110β in early adaptive responses to p110α-specific inhibitors in luminal breast cancer.
    Cancer Cell. 2015 Jan 12;27(1):97-108 PMID: 25544637
  62. The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism.
    Nat Rev Genet. 2006 Aug;7(8):606-19 PMID: 16847462
  63. JAK2/STAT5 inhibition circumvents resistance to PI3K/mTOR blockade: a rationale for cotargeting these pathways in metastatic breast cancer.
    Cancer Cell. 2012 Dec 11;22(6):796-811 PMID: 23238015
  64. Hypoxia-inducible factor determines sensitivity to inhibitors of mTOR in kidney cancer.
    Nat Med. 2006 Jan;12 (1):122-7 PMID: 16341243
  65. Combined Inhibition of Both p110α and p110β Isoforms of Phosphatidylinositol 3-Kinase Is Required for Sustained Therapeutic Effect in PTEN-Deficient, ER+ Breast Cancer.
    Clin Cancer Res. 2017 Jun 1;23 (11):2795-2805 PMID: 27903677
  66. Deconvolution of Buparlisib's mechanism of action defines specific PI3K and tubulin inhibitors for therapeutic intervention.
    Nat Commun. 2017 Mar 09;8:14683 PMID: 28276440
  67. Response and acquired resistance to everolimus in anaplastic thyroid cancer.
    N Engl J Med. 2014 Oct 9;371(15):1426-33 PMID: 25295501
  68. Rapamycin activation of 4E-BP prevents parkinsonian dopaminergic neuron loss.
    Nat Neurosci. 2009 Sep;12 (9):1129-35 PMID: 19684592
  69. Multiregion Whole-Exome Sequencing Uncovers the Genetic Evolution and Mutational Heterogeneity of Early-Stage Metastatic Melanoma.
    Cancer Res. 2016 Aug 15;76(16):4765-74 PMID: 27216186
  70. PI3Kδ and primary immunodeficiencies.
    Nat Rev Immunol. 2016 Nov;16(11):702-714 PMID: 27616589
  71. Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex.
    Science. 2005 Feb 18;307(5712):1098-101 PMID: 15718470
  72. PI3K-targeted therapy can be evaded by gene amplification along the MYC-eukaryotic translation initiation factor 4E (eIF4E) axis.
    Proc Natl Acad Sci U S A. 2011 Sep 13;108(37):E699-708 PMID: 21876152
  73. BTK regulates PtdIns-4,5-P2 synthesis: importance for calcium signaling and PI3K activity.
    Immunity. 2003 Nov;19(5):669-78 PMID: 14614854
  74. Feedback upregulation of HER3 (ErbB3) expression and activity attenuates antitumor effect of PI3K inhibitors.
    Proc Natl Acad Sci U S A. 2012 Feb 21;109(8):2718-23 PMID: 21368164
  75. Clonal status of actionable driver events and the timing of mutational processes in cancer evolution.
    Sci Transl Med. 2015 Apr 15;7(283):283ra54 PMID: 25877892
  76. PI3Kβ plays a critical role in neutrophil activation by immune complexes.
    Sci Signal. 2011 Apr 12;4(168):ra23 PMID: 21487106
  77. A phase 1 study of the sachet formulation of the oral dual PI3K/mTOR inhibitor BEZ235 given twice daily (BID) in patients with advanced solid tumors.
    Invest New Drugs. 2015 Apr;33(2):463-71 PMID: 25707361
  78. PI3K inhibition results in enhanced estrogen receptor function and dependence in hormone receptor-positive breast cancer.
    Sci Transl Med. 2015 Apr 15;7(283):283ra51 PMID: 25877889
  79. Activating Mutations in PIK3CB Confer Resistance to PI3K Inhibition and Define a Novel Oncogenic Role for p110β.
    Cancer Res. 2016 Mar 1;76(5):1193-203 PMID: 26759240
  80. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia.
    N Engl J Med. 2013 Jul 4;369(1):32-42 PMID: 23782158
  81. The 4E-BP-eIF4E axis promotes rapamycin-sensitive growth and proliferation in lymphocytes.
    Sci Signal. 2016 May 31;9(430):ra57 PMID: 27245614
  82. PDK1-SGK1 Signaling Sustains AKT-Independent mTORC1 Activation and Confers Resistance to PI3Kα Inhibition.
    Cancer Cell. 2016 Aug 8;30(2):229-242 PMID: 27451907
  83. Sequential activation of class IB and class IA PI3K is important for the primed respiratory burst of human but not murine neutrophils.
    Blood. 2005 Aug 15;106(4):1432-40 PMID: 15878979
  84. PARK2 Depletion Connects Energy and Oxidative Stress to PI3K/Akt Activation via PTEN S-Nitrosylation.
    Mol Cell. 2017 Mar 16;65(6):999-1013.e7 PMID: 28306514
  85. MAPK, phosphatidylinositol 3-kinase, and mammalian target of rapamycin pathways converge at the level of ribosomal protein S6 phosphorylation to control metabolic signaling in CD8 T cells.
    J Immunol. 2009 Dec 1;183(11):7388-97 PMID: 19917692
  86. A phase I dose-escalation study to assess safety, tolerability, pharmacokinetics, and preliminary efficacy of the dual mTORC1/mTORC2 kinase inhibitor CC-223 in patients with advanced solid tumors or multiple myeloma.
    Cancer. 2015 Oct 1;121(19):3481-90 PMID: 26177599
  87. PI(3,4,5)P3 Engagement Restricts Akt Activity to Cellular Membranes.
    Mol Cell. 2017 Feb 2;65(3):416-431.e6 PMID: 28157504
  88. ICOS coreceptor signaling inactivates the transcription factor FOXO1 to promote Tfh cell differentiation.
    Immunity. 2015 Feb 17;42(2):239-251 PMID: 25692700
  89. PI3K in lymphocyte development, differentiation and activation.
    Nat Rev Immunol. 2003 Apr;3(4):317-30 PMID: 12669022
  90. Functional characterization of an isoform-selective inhibitor of PI3K-p110β as a potential anticancer agent.
    Cancer Discov. 2012 May;2(5):425-33 PMID: 22588880
  91. BCR signaling inhibitors differ in their ability to overcome Mcl-1-mediated resistance of CLL B cells to ABT-199.
    Blood. 2016 Jun 23;127(25):3192-201 PMID: 27095788
  92. A central role for GRB10 in regulation of islet function in man.
    PLoS Genet. 2014 Apr 03;10(4):e1004235 PMID: 24699409
  93. Evidence that the Rous sarcoma virus transforming gene product phosphorylates phosphatidylinositol and diacylglycerol.
    Proc Natl Acad Sci U S A. 1984 Apr;81(7):2117-21 PMID: 6326105
  94. PI3K in cancer: divergent roles of isoforms, modes of activation and therapeutic targeting.
    Nat Rev Cancer. 2015 Jan;15(1):7-24 PMID: 25533673
  95. A Kinase Inhibitor Targeted to mTORC1 Drives Regression in Glioblastoma.
    Cancer Cell. 2017 Mar 13;31(3):424-435 PMID: 28292440
  96. Discovery and saturation analysis of cancer genes across 21 tumour types.
    Nature. 2014 Jan 23;505(7484):495-501 PMID: 24390350
  97. Overcoming resistance to checkpoint blockade therapy by targeting PI3Kγ in myeloid cells.
    Nature. 2016 Nov 17;539(7629):443-447 PMID: 27828943
  98. Targeted therapy in rare cancers--adopting the orphans.
    Nat Rev Clin Oncol. 2012 Nov;9(11):631-42 PMID: 22965154
  99. P-Rex1 directly activates RhoG to regulate GPCR-driven Rac signalling and actin polarity in neutrophils.
    J Cell Sci. 2014 Jun 1;127(Pt 11):2589-600 PMID: 24659802
  100. Critical role for the p110alpha phosphoinositide-3-OH kinase in growth and metabolic regulation.
    Nature. 2006 May 18;441(7091):366-70 PMID: 16625210
  101. Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma.
    Oncotarget. 2014 May 15;5(9):2355-71 PMID: 24796395
  102. PI3Kδ inhibition reduces TNF secretion and neuroinflammation in a mouse cerebral stroke model.
    Nat Commun. 2014 Mar 14;5:3450 PMID: 24625684
  103. mTORC1 and mTORC2 selectively regulate CD8⁺ T cell differentiation.
    J Clin Invest. 2015 May;125(5):2090-108 PMID: 25893604
  104. Modulation of epithelial neoplasia and lymphoid hyperplasia in PTEN+/- mice by the p85 regulatory subunits of phosphoinositide 3-kinase.
    Proc Natl Acad Sci U S A. 2005 Jul 19;102(29):10238-43 PMID: 16006513
  105. Intermittent High-Dose Scheduling of AZD8835, a Novel Selective Inhibitor of PI3Kα and PI3Kδ, Demonstrates Treatment Strategies for PIK3CA-Dependent Breast Cancers.
    Mol Cancer Ther. 2016 May;15(5):877-89 PMID: 26839307
  106. mTOR is a key modulator of ageing and age-related disease.
    Nature. 2013 Jan 17;493(7432):338-45 PMID: 23325216
  107. Akt-directed glucose metabolism can prevent Bax conformation change and promote growth factor-independent survival.
    Mol Cell Biol. 2003 Oct;23(20):7315-28 PMID: 14517300
  108. PI3K inhibition impairs BRCA1/2 expression and sensitizes BRCA-proficient triple-negative breast cancer to PARP inhibition.
    Cancer Discov. 2012 Nov;2(11):1036-47 PMID: 22915752
  109. Akt phosphorylates HK-II at Thr-473 and increases mitochondrial HK-II association to protect cardiomyocytes.
    J Biol Chem. 2013 Aug 16;288(33):23798-806 PMID: 23836898
  110. Idelalisib--a PI3Kδ inhibitor for B-cell cancers.
    N Engl J Med. 2014 Mar 13;370(11):1061-2 PMID: 24620870
  111. Increased insulin sensitivity and hypoglycaemia in mice lacking the p85 alpha subunit of phosphoinositide 3-kinase.
    Nat Genet. 1999 Feb;21(2):230-5 PMID: 9988280
  112. Inhibition of PI3K/mTOR leads to adaptive resistance in matrix-attached cancer cells.
    Cancer Cell. 2012 Feb 14;21(2):227-39 PMID: 22340595
  113. RNAi screen identifies Brd4 as a therapeutic target in acute myeloid leukaemia.
    Nature. 2011 Aug 03;478(7370):524-8 PMID: 21814200
  114. SGK3 mediates INPP4B-dependent PI3K signaling in breast cancer.
    Mol Cell. 2014 Nov 20;56(4):595-607 PMID: 25458846
  115. Kinome-Wide RNA Interference Screen Reveals a Role for PDK1 in Acquired Resistance to CDK4/6 Inhibition in ER-Positive Breast Cancer.
    Cancer Res. 2017 May 1;77(9):2488-2499 PMID: 28249908
  116. Tumor genetic analyses of patients with metastatic renal cell carcinoma and extended benefit from mTOR inhibitor therapy.
    Clin Cancer Res. 2014 Apr 1;20(7):1955-64 PMID: 24622468
  117. Control of PD-L1 Expression by Oncogenic Activation of the AKT-mTOR Pathway in Non-Small Cell Lung Cancer.
    Cancer Res. 2016 Jan 15;76(2):227-38 PMID: 26637667
  118. Akt1 and Akt2 promote peripheral B-cell maturation and survival.
    Blood. 2010 May 20;115(20):4043-50 PMID: 20042722
  119. Ibrutinib-induced lymphocytosis in patients with chronic lymphocytic leukemia: correlative analyses from a phase II study.
    Leukemia. 2014 Nov;28(11):2188-96 PMID: 24699307
  120. Integrated Multiregional Analysis Proposing a New Model of Colorectal Cancer Evolution.
    PLoS Genet. 2016 Feb 18;12(2):e1005778 PMID: 26890883
  121. Molecular and Functional Characterization of Three Different Postzygotic Mutations in PIK3CA-Related Overgrowth Spectrum (PROS) Patients: Effects on PI3K/AKT/mTOR Signaling and Sensitivity to PIK3 Inhibitors.
    PLoS One. 2015 Apr 27;10(4):e0123092 PMID: 25915946
  122. PI3K-Akt-mTORC1-S6K1/2 axis controls Th17 differentiation by regulating Gfi1 expression and nuclear translocation of RORγ.
    Cell Rep. 2012 Apr 19;1(4):360-73 PMID: 22832227
  123. Phosphorylation of TXNIP by AKT Mediates Acute Influx of Glucose in Response to Insulin.
    Cell Rep. 2017 Jun 6;19(10 ):2005-2013 PMID: 28591573
  124. A Phase Ib Study of Alpelisib (BYL719), a PI3Kα-Specific Inhibitor, with Letrozole in ER+/HER2- Metastatic Breast Cancer.
    Clin Cancer Res. 2017 Jan 1;23 (1):26-34 PMID: 27126994
  125. The GLUT4 glucose transporter.
    Cell Metab. 2007 Apr;5(4):237-52 PMID: 17403369
  126. The blockade of immune checkpoints in cancer immunotherapy.
    Nat Rev Cancer. 2012 Mar 22;12(4):252-64 PMID: 22437870
  127. Conformational disruption of PI3Kδ regulation by immunodeficiency mutations in PIK3CD and PIK3R1.
    Proc Natl Acad Sci U S A. 2017 Feb 21;114(8):1982-1987 PMID: 28167755
  128. BET bromodomain inhibition as a therapeutic strategy to target c-Myc.
    Cell. 2011 Sep 16;146(6):904-17 PMID: 21889194
  129. Buparlisib, a PI3K inhibitor, demonstrates acceptable tolerability and preliminary activity in a phase I trial of patients with advanced leukemias.
    Am J Hematol. 2017 Jan;92 (1):7-11 PMID: 27673440
  130. BRCAness revisited.
    Nat Rev Cancer. 2016 Feb;16(2):110-20 PMID: 26775620
  131. Activation of the PI3K/mTOR Pathway following PARP Inhibition in Small Cell Lung Cancer.
    PLoS One. 2016 Apr 07;11(4):e0152584 PMID: 27055253
  132. Feedback suppression of PI3Kα signaling in PTEN-mutated tumors is relieved by selective inhibition of PI3Kβ.
    Cancer Cell. 2015 Jan 12;27(1):109-22 PMID: 25544636
  133. Phase I, dose-escalation study of BKM120, an oral pan-Class I PI3K inhibitor, in patients with advanced solid tumors.
    J Clin Oncol. 2012 Jan 20;30(3):282-90 PMID: 22162589
  134. TAK-228 (formerly MLN0128), an investigational oral dual TORC1/2 inhibitor: A phase I dose escalation study in patients with relapsed or refractory multiple myeloma, non-Hodgkin lymphoma, or Waldenström's macroglobulinemia.
    Am J Hematol. 2016 Jun;91(4):400-5 PMID: 26800393
  135. Mosaic Disorders of the PI3K/PTEN/AKT/TSC/mTORC1 Signaling Pathway.
    Dermatol Clin. 2017 Jan;35(1):51-60 PMID: 27890237
  136. Association of phosphatidylinositol kinase activity with polyoma middle-T competent for transformation.
    Nature. 1985 May 16-22;315(6016):239-42 PMID: 2987699
  137. Context-Specific Function of S6K2 in Th Cell Differentiation.
    J Immunol. 2016 Oct 15;197(8):3049-3058 PMID: 27613697
  138. Asymmetric PI3K Signaling Driving Developmental and Regenerative Cell Fate Bifurcation.
    Cell Rep. 2015 Dec 15;13(10):2203-18 PMID: 26628372
  139. Akt and mTOR in B Cell Activation and Differentiation.
    Front Immunol. 2012 Aug 06;3:228 PMID: 22888331
  140. Obesity and Cancer Mechanisms: Cancer Metabolism.
    J Clin Oncol. 2016 Dec 10;34(35):4277-4283 PMID: 27903152
  141. Phosphoinositide 3-kinase activity in T cells regulates the magnitude of the germinal center reaction.
    J Immunol. 2010 Oct 1;185(7):4042-52 PMID: 20826752
  142. Dual mTORC1/2 and HER2 blockade results in antitumor activity in preclinical models of breast cancer resistant to anti-HER2 therapy.
    Clin Cancer Res. 2012 May 1;18(9):2603-12 PMID: 22407832
  143. A phosphatidylinositol-3-OH kinase family member regulating longevity and diapause in Caenorhabditis elegans.
    Nature. 1996 Aug 8;382(6591):536-9 PMID: 8700226
  144. AKT inhibition relieves feedback suppression of receptor tyrosine kinase expression and activity.
    Cancer Cell. 2011 Jan 18;19(1):58-71 PMID: 21215704
  145. Mechanism of two classes of cancer mutations in the phosphoinositide 3-kinase catalytic subunit.
    Science. 2007 Jul 13;317(5835):239-42 PMID: 17626883
  146. Phosphatidylinositol 3-kinase δ blockade increases genomic instability in B cells.
    Nature. 2017 Feb 23;542(7642):489-493 PMID: 28199309
  147. Activation of a metabolic gene regulatory network downstream of mTOR complex 1.
    Mol Cell. 2010 Jul 30;39(2):171-83 PMID: 20670887
  148. Deregulation of glucose transporter 1 and glycolytic gene expression by c-Myc.
    J Biol Chem. 2000 Jul 21;275(29):21797-800 PMID: 10823814
  149. Macrophage PI3Kγ Drives Pancreatic Ductal Adenocarcinoma Progression.
    Cancer Discov. 2016 Aug;6(8):870-85 PMID: 27179037
  150. Intratumoral delivery of mTORC2-deficient dendritic cells inhibits B16 melanoma growth by promoting CD8(+) effector T cell responses.
    Oncoimmunology. 2016 Mar 23;5(6):e1146841 PMID: 27471613
  151. PI3 Kinase and FOXO1 Transcription Factor Activity Differentially Control B Cells in the Germinal Center Light and Dark Zones.
    Immunity. 2015 Dec 15;43(6):1075-86 PMID: 26620760
  152. Phosphorylation and activation of heart 6-phosphofructo-2-kinase by protein kinase B and other protein kinases of the insulin signaling cascades.
    J Biol Chem. 1997 Jul 11;272(28):17269-75 PMID: 9211863
  153. Overcoming mTOR resistance mutations with a new-generation mTOR inhibitor.
    Nature. 2016 May 18;534(7606):272-6 PMID: 27279227
  154. Interleukin-3-mediated cell survival signals include phosphatidylinositol 3-kinase-dependent translocation of the glucose transporter GLUT1 to the cell surface.
    J Biol Chem. 2003 Oct 10;278(41):39337-48 PMID: 12869574
  155. p(⁷⁰S⁶K¹) in the TORC1 pathway is essential for the differentiation of Th17 Cells, but not Th1, Th2, or Treg cells in mice.
    Eur J Immunol. 2016 Jan;46(1):212-22 PMID: 26514620
  156. The PI3K isoforms p110alpha and p110delta are essential for pre-B cell receptor signaling and B cell development.
    Sci Signal. 2010 Aug 10;3(134):ra60 PMID: 20699475
  157. PI3K pathway regulates ER-dependent transcription in breast cancer through the epigenetic regulator KMT2D.
    Science. 2017 Mar 24;355(6331):1324-1330 PMID: 28336670
  158. Clonal Heterogeneity and Tumor Evolution: Past, Present, and the Future.
    Cell. 2017 Feb 9;168(4):613-628 PMID: 28187284
  159. Coincident signals from GPCRs and receptor tyrosine kinases are uniquely transduced by PI3Kβ in myeloid cells.
    Sci Signal. 2016 Aug 16;9(441):ra82 PMID: 27531651
  160. MYC suppresses cancer metastasis by direct transcriptional silencing of αv and β3 integrin subunits.
    Nat Cell Biol. 2012 May 13;14(6):567-74 PMID: 22581054
  161. SIN1/MIP1 maintains rictor-mTOR complex integrity and regulates Akt phosphorylation and substrate specificity.
    Cell. 2006 Oct 6;127(1):125-37 PMID: 16962653
  162. Combining a PI3K inhibitor with a PARP inhibitor provides an effective therapy for BRCA1-related breast cancer.
    Cancer Discov. 2012 Nov;2(11):1048-63 PMID: 22915751
  163. Proteomic markers of DNA repair and PI3K pathway activation predict response to the PARP inhibitor BMN 673 in small cell lung cancer.
    Clin Cancer Res. 2013 Nov 15;19(22):6322-8 PMID: 24077350
  164. Chronic signaling via the metabolic checkpoint kinase mTORC1 induces macrophage granuloma formation and marks sarcoidosis progression.
    Nat Immunol. 2017 Mar;18(3):293-302 PMID: 28092373
  165. A role for phosphoinositol 3-kinase delta in the impairment of glucocorticoid responsiveness in patients with chronic obstructive pulmonary disease.
    J Allergy Clin Immunol. 2010 May;125(5):1146-53 PMID: 20381852
  166. mTORC1 inhibition is required for sensitivity to PI3K p110α inhibitors in PIK3CA-mutant breast cancer.
    Sci Transl Med. 2013 Jul 31;5(196):196ra99 PMID: 23903756
  167. Foxo transcription factors control regulatory T cell development and function.
    Immunity. 2010 Dec 14;33(6):890-904 PMID: 21167754
  168. PI3Kgamma inhibition: towards an 'aspirin of the 21st century'?
    Nat Rev Drug Discov. 2006 Nov;5(11):903-18 PMID: 17080027
  169. Cancer immunotherapy: the beginning of the end of cancer?
    BMC Med. 2016 May 05;14 :73 PMID: 27151159
  170. Bruton Tyrosine Kinase-Dependent Immune Cell Cross-talk Drives Pancreas Cancer.
    Cancer Discov. 2016 Mar;6(3):270-85 PMID: 26715645
  171. Targeting PI3K in Cancer: Impact on Tumor Cells, Their Protective Stroma, Angiogenesis, and Immunotherapy.
    Cancer Discov. 2016 Oct;6(10 ):1090-1105 PMID: 27655435
  172. The PI3K pathway in B cell metabolism.
    Crit Rev Biochem Mol Biol. 2016 Sep;51(5):359-378 PMID: 27494162
  173. CDK4/6 inhibitors have potent activity in combination with pathway selective therapeutic agents in models of pancreatic cancer.
    Oncotarget. 2014 Aug 15;5(15):6512-25 PMID: 25156567
  174. The p110delta isoform of phosphoinositide 3-kinase controls clonal expansion and differentiation of Th cells.
    J Immunol. 2006 Oct 15;177(8):5122-8 PMID: 17015696
  175. Efficacy and Safety of Sirolimus in the Treatment of Complicated Vascular Anomalies.
    Pediatrics. 2016 Feb;137(2):e20153257 PMID: 26783326
  176. RAPping production of type I interferon in pDCs through mTOR.
    Nat Immunol. 2008 Oct;9(10):1097-9 PMID: 18800159
  177. Molecular Alterations and Everolimus Efficacy in Human Epidermal Growth Factor Receptor 2-Overexpressing Metastatic Breast Cancers: Combined Exploratory Biomarker Analysis From BOLERO-1 and BOLERO-3.
    J Clin Oncol. 2016 Jun 20;34(18):2115-24 PMID: 27091708
  178. AKT/PKB Signaling: Navigating the Network.
    Cell. 2017 Apr 20;169(3):381-405 PMID: 28431241
  179. Activation of mammalian target of rapamycin in transformed B lymphocytes is nutrient dependent but independent of Akt, mitogen-activated protein kinase/extracellular signal-regulated kinase kinase, insulin growth factor-I, and serum.
    Cancer Res. 2005 Sep 1;65(17):7800-8 PMID: 16140948
  180. mTOR, metabolism, and the regulation of T-cell differentiation and function.
    Immunol Rev. 2012 Sep;249(1):43-58 PMID: 22889214
  181. Vulnerabilities of PTEN-TP53-deficient prostate cancers to compound PARP-PI3K inhibition.
    Cancer Discov. 2014 Aug;4(8):896-904 PMID: 24866151
  182. Regulation of class-switch recombination and plasma cell differentiation by phosphatidylinositol 3-kinase signaling.
    Immunity. 2006 Oct;25(4):545-57 PMID: 17000121
  183. High frequency of mutations of the PIK3CA gene in human cancers.
    Science. 2004 Apr 23;304(5670):554 PMID: 15016963
  184. Distinct signaling mechanisms activate the target of rapamycin in response to different B-cell stimuli.
    Eur J Immunol. 2007 Oct;37(10):2923-36 PMID: 17724683
  185. Control of amino-acid transport by antigen receptors coordinates the metabolic reprogramming essential for T cell differentiation.
    Nat Immunol. 2013 May;14(5):500-8 PMID: 23525088
  186. TORC1 suppression predicts responsiveness to RAF and MEK inhibition in BRAF-mutant melanoma.
    Sci Transl Med. 2013 Jul 31;5(196 ):196ra98 PMID: 23903755
  187. Regulation of innate immune cell function by mTOR.
    Nat Rev Immunol. 2015 Oct;15(10):599-614 PMID: 26403194
  188. Loss of class IA PI3K signaling in muscle leads to impaired muscle growth, insulin response, and hyperlipidemia.
    Cell Metab. 2006 May;3(5):355-66 PMID: 16679293
  189. Inhibition of mTORC1 leads to MAPK pathway activation through a PI3K-dependent feedback loop in human cancer.
    J Clin Invest. 2008 Sep;118(9):3065-74 PMID: 18725988
  190. Kinase and BET Inhibitors Together Clamp Inhibition of PI3K Signaling and Overcome Resistance to Therapy.
    Cancer Cell. 2015 Jun 8;27(6):837-51 PMID: 26058079
  191. The Rab GTPase-activating protein AS160 as a common regulator of insulin- and Galphaq-mediated intracellular GLUT4 vesicle distribution.
    Endocr J. 2009;56(3):345-59 PMID: 19139597
  192. Hypoglycaemia, liver necrosis and perinatal death in mice lacking all isoforms of phosphoinositide 3-kinase p85 alpha.
    Nat Genet. 2000 Nov;26(3):379-82 PMID: 11062485
  193. Signaling through Itk promotes T helper 2 differentiation via negative regulation of T-bet.
    Immunity. 2004 Jul;21(1):67-80 PMID: 15345221
  194. Immunotherapy with PI3K inhibitor and Toll-like receptor agonist induces IFN-γ+IL-17+ polyfunctional T cells that mediate rejection of murine tumors.
    Cancer Res. 2012 Feb 1;72(3):581-91 PMID: 22158905
  195. Lymphocyte fate specification as a deterministic but highly plastic process.
    Nat Rev Immunol. 2014 Oct;14 (10 ):699-704 PMID: 25190286
  196. Ribosomal protein S6 kinase 1 signaling regulates mammalian life span.
    Science. 2009 Oct 2;326(5949):140-4 PMID: 19797661
  197. Spatial and temporal diversity in genomic instability processes defines lung cancer evolution.
    Science. 2014 Oct 10;346(6206):251-6 PMID: 25301630
  198. The p85 regulatory subunit of phosphoinositide 3-kinase down-regulates IRS-1 signaling via the formation of a sequestration complex.
    J Cell Biol. 2005 Aug 1;170(3):455-64 PMID: 16043515
  199. Essential role for the p110delta phosphoinositide 3-kinase in the allergic response.
    Nature. 2004 Oct 21;431(7011):1007-11 PMID: 15496927
  200. Regulation and cellular functions of class II phosphoinositide 3-kinases.
    Biochem J. 2012 May 1;443(3):587-601 PMID: 22507127
  201. Emerging role of mTOR in the response to cancer therapeutics.
    Trends Cancer. 2016 May;2(5):241-251 PMID: 27668290
  202. PTEN opposes negative selection and enables oncogenic transformation of pre-B cells.
    Nat Med. 2016 Apr;22(4):379-87 PMID: 26974310
  203. PI3K and MEK inhibitor combinations: examining the evidence in selected tumor types.
    Cancer Chemother Pharmacol. 2013 Jun;71(6):1395-409 PMID: 23443307
  204. A Phase II Study of BEZ235 in Patients with Everolimus-resistant, Advanced Pancreatic Neuroendocrine Tumours.
    Anticancer Res. 2016 Feb;36(2):713-9 PMID: 26851029
  205. Type I phosphatidylinositol kinase makes a novel inositol phospholipid, phosphatidylinositol-3-phosphate.
    Nature. 1988 Apr 14;332(6165):644-6 PMID: 2833705
  206. Long-term treatment of epilepsy with everolimus in tuberous sclerosis.
    Neurology. 2016 Dec 6;87(23 ):2408-2415 PMID: 27815402
  207. Differentiation of CD8 memory T cells depends on Foxo1.
    J Exp Med. 2013 Jun 3;210(6):1189-200 PMID: 23712431
  208. Does the PI3K pathway promote or antagonize regulatory T cell development and function?
    Front Immunol. 2012 Aug 14;3:244 PMID: 22912633
  209. CD4+ T cell effector commitment coupled to self-renewal by asymmetric cell divisions.
    J Exp Med. 2017 Jan;214(1):39-47 PMID: 27923906
  210. Targeting MYC dependence in cancer by inhibiting BET bromodomains.
    Proc Natl Acad Sci U S A. 2011 Oct 4;108(40):16669-74 PMID: 21949397
  211. Key proteins and pathways that regulate lifespan.
    J Biol Chem. 2017 Apr 21;292(16):6452-6460 PMID: 28264931
  212. Cancer-derived mutations in the regulatory subunit p85alpha of phosphoinositide 3-kinase function through the catalytic subunit p110alpha.
    Proc Natl Acad Sci U S A. 2010 Aug 31;107(35):15547-52 PMID: 20713702
  213. FoxO transcription factors promote AKT Ser473 phosphorylation and renal tumor growth in response to pharmacologic inhibition of the PI3K-AKT pathway.
    Cancer Res. 2014 Mar 15;74(6):1682-93 PMID: 24448243
  214. Pneumocystis jirovecii pneumonia in everolimus-treated renal cell carcinoma.
    J Clin Oncol. 2015 Mar 10;33(8):e45-7 PMID: 24638002
  215. Next-generation sequencing reveals somatic mutations that confer exceptional response to everolimus.
    Oncotarget. 2016 Mar 1;7(9):10547-56 PMID: 26859683
  216. Transformation of chicken cells by the gene encoding the catalytic subunit of PI 3-kinase.
    Science. 1997 Jun 20;276(5320):1848-50 PMID: 9188528
  217. Functional Genomic Landscape of Human Breast Cancer Drivers, Vulnerabilities, and Resistance.
    Cell. 2016 Jan 14;164(1-2):293-309 PMID: 26771497
  218. Buparlisib plus fulvestrant versus placebo plus fulvestrant in postmenopausal, hormone receptor-positive, HER2-negative, advanced breast cancer (BELLE-2): a randomised, double-blind, placebo-controlled, phase 3 trial.
    Lancet Oncol. 2017 Jul;18(7):904-916 PMID: 28576675
  219. Phosphoproteomic Analyses of Interleukin 2 Signaling Reveal Integrated JAK Kinase-Dependent and -Independent Networks in CD8(+) T Cells.
    Immunity. 2016 Sep 20;45(3):685-700 PMID: 27566939
  220. Everolimus for subependymal giant cell astrocytoma in patients with tuberous sclerosis complex: 2-year open-label extension of the randomised EXIST-1 study.
    Lancet Oncol. 2014 Dec;15(13):1513-20 PMID: 25456370
  221. Characterization of the novel and specific PI3Kα inhibitor NVP-BYL719 and development of the patient stratification strategy for clinical trials.
    Mol Cancer Ther. 2014 May;13(5):1117-29 PMID: 24608574
  222. AZD2014, an Inhibitor of mTORC1 and mTORC2, Is Highly Effective in ER+ Breast Cancer When Administered Using Intermittent or Continuous Schedules.
    Mol Cancer Ther. 2015 Nov;14(11):2508-18 PMID: 26358751
  223. Lenalidomide, idelalisib, and rituximab are unacceptably toxic in patients with relapsed/refractory indolent lymphoma.
    Blood. 2015 May 21;125(21):3357-9 PMID: 25999447
  224. Distinct functions for the transcription factor Foxo1 at various stages of B cell differentiation.
    Nat Immunol. 2008 Dec;9(12 ):1388-98 PMID: 18978794
  225. mTOR Signaling in Growth, Metabolism, and Disease.
    Cell. 2017 Mar 9;168(6):960-976 PMID: 28283069
  226. PDGF-dependent tyrosine phosphorylation stimulates production of novel polyphosphoinositides in intact cells.
    Cell. 1989 Apr 7;57(1):167-75 PMID: 2467744
  227. The mTOR-regulated phosphoproteome reveals a mechanism of mTORC1-mediated inhibition of growth factor signaling.
    Science. 2011 Jun 10;332(6035):1317-22 PMID: 21659604
  228. Foxo1 directly regulates the transcription of recombination-activating genes during B cell development.
    Nat Immunol. 2008 Jun;9(6):613-22 PMID: 18469817
  229. Metabolic maintenance of cell asymmetry following division in activated T lymphocytes.
    Nature. 2016 Apr 21;532(7599):389-93 PMID: 27064903
  230. mTORC1-mediated cell proliferation, but not cell growth, controlled by the 4E-BPs.
    Science. 2010 May 28;328(5982):1172-6 PMID: 20508131
  231. Inactivation of PI(3)K p110δ breaks regulatory T-cell-mediated immune tolerance to cancer.
    Nature. 2014 Jun 19;510(7505):407-411 PMID: 24919154
  232. Characterization of VPS34, a gene required for vacuolar protein sorting and vacuole segregation in Saccharomyces cerevisiae.
    Mol Cell Biol. 1990 Dec;10(12):6742-54 PMID: 2247081
  233. PI3Kγ is a molecular switch that controls immune suppression.
    Nature. 2016 Nov 17;539(7629):437-442 PMID: 27642729
  234. PTEN.
    Annu Rev Biochem. 2014;83:641-69 PMID: 24905788
  235. Effective use of PI3K inhibitor BKM120 and PARP inhibitor Olaparib to treat PIK3CA mutant ovarian cancer.
    Oncotarget. 2016 Mar 15;7(11):13153-66 PMID: 26909613
  236. Regulation and function of ribosomal protein S6 kinase (S6K) within mTOR signalling networks.
    Biochem J. 2012 Jan 1;441(1):1-21 PMID: 22168436
  237. Idelalisib and rituximab in relapsed chronic lymphocytic leukemia.
    N Engl J Med. 2014 Mar 13;370(11):997-1007 PMID: 24450857
  238. Tuberous sclerosis complex: From molecular biology to novel therapeutic approaches.
    IUBMB Life. 2016 Dec;68(12 ):955-962 PMID: 27797139
  239. The FOXO1 Transcription Factor Instructs the Germinal Center Dark Zone Program.
    Immunity. 2015 Dec 15;43(6):1064-74 PMID: 26620759
  240. Genomic Characterization of Brain Metastases Reveals Branched Evolution and Potential Therapeutic Targets.
    Cancer Discov. 2015 Nov;5(11):1164-1177 PMID: 26410082
  241. The roles of PINK1, parkin, and mitochondrial fidelity in Parkinson's disease.
    Neuron. 2015 Jan 21;85(2):257-73 PMID: 25611507
  242. mTOR kinase inhibitors promote antibody class switching via mTORC2 inhibition.
    Proc Natl Acad Sci U S A. 2014 Nov 25;111(47):E5076-85 PMID: 25385646
  243. Management of adverse events associated with idelalisib treatment: expert panel opinion.
    Leuk Lymphoma. 2015;56(10):2779-86 PMID: 25726955
  244. Genome sequencing identifies a basis for everolimus sensitivity.
    Science. 2012 Oct 12;338(6104):221 PMID: 22923433
  245. Molecular Pathways: The eIF4F Translation Initiation Complex-New Opportunities for Cancer Treatment.
    Clin Cancer Res. 2017 Jan 1;23 (1):21-25 PMID: 27789529
  246. A Phase I Trial of BKM120 (Buparlisib) in Combination with Fulvestrant in Postmenopausal Women with Estrogen Receptor-Positive Metastatic Breast Cancer.
    Clin Cancer Res. 2016 Apr 1;22(7):1583-91 PMID: 26563128
  247. The promise of combining inhibition of PI3K and PARP as cancer therapy.
    Cancer Discov. 2012 Nov;2(11):982-4 PMID: 23148373
  248. TSC1 activates TGF-β-Smad2/3 signaling in growth arrest and epithelial-to-mesenchymal transition.
    Dev Cell. 2015 Mar 9;32(5):617-30 PMID: 25727005
  249. Efficacy and safety of sirolimus in lymphangioleiomyomatosis.
    N Engl J Med. 2011 Apr 28;364(17):1595-606 PMID: 21410393
  250. Idelalisib given front-line for treatment of chronic lymphocytic leukemia causes frequent immune-mediated hepatotoxicity.
    Blood. 2016 Jul 14;128(2):195-203 PMID: 27247136
  251. Phase 2 study of idelalisib and entospletinib: pneumonitis limits combination therapy in relapsed refractory CLL and NHL.
    Blood. 2016 May 19;127(20):2411-5 PMID: 26968534
  252. Lymphangioleiomyomatosis - a wolf in sheep's clothing.
    J Clin Invest. 2012 Nov;122(11):3807-16 PMID: 23114603
  253. Convergent loss of PTEN leads to clinical resistance to a PI(3)Kα inhibitor.
    Nature. 2015 Feb 12;518(7538):240-4 PMID: 25409150
  254. Topical Use of Mammalian Target of Rapamycin (mTOR) Inhibitors in Tuberous Sclerosis Complex-A Comprehensive Review of the Literature.
    Pediatr Neurol. 2016 Aug;61:21-7 PMID: 27222056
  255. The p110δ isoform of the kinase PI(3)K controls the subcellular compartmentalization of TLR4 signaling and protects from endotoxic shock.
    Nat Immunol. 2012 Nov;13(11):1045-1054 PMID: 23023391
  256. Impaired B and T cell antigen receptor signaling in p110delta PI 3-kinase mutant mice.
    Science. 2002 Aug 9;297(5583):1031-4 PMID: 12130661
  257. Xid-like phenotypes: a B cell signalosome takes shape.
    Immunity. 2000 Jul;13(1):1-3 PMID: 10933389
  258. Mutations in the adaptor-binding domain and associated linker region of p110δ cause Activated PI3K-δ Syndrome 1 (APDS1).
    Haematologica. 2017 Jul;102(7):e278-e281 PMID: 28428270
  259. mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt.
    Cancer Res. 2006 Feb 1;66(3):1500-8 PMID: 16452206
  260. The age-1 and daf-2 genes function in a common pathway to control the lifespan of Caenorhabditis elegans.
    Genetics. 1995 Dec;141(4):1399-406 PMID: 8601482
  261. Differential PI3Kδ Signaling in CD4+ T-cell Subsets Enables Selective Targeting of T Regulatory Cells to Enhance Cancer Immunotherapy.
    Cancer Res. 2017 Apr 15;77(8):1892-1904 PMID: 28108509
  262. Genetic basis of Cowden syndrome and its implications for clinical practice and risk management.
    Appl Clin Genet. 2016 Jul 13;9:83-92 PMID: 27471403
  263. The regulation of class IA PI 3-kinases by inter-subunit interactions.
    Curr Top Microbiol Immunol. 2010;346:87-114 PMID: 20544340
  264. New developments in the genetics and pathogenesis of tumours in tuberous sclerosis complex.
    J Pathol. 2017 Jan;241(2):219-225 PMID: 27753446
  265. Safety and tolerability of AZD5363 in Japanese patients with advanced solid tumors.
    Cancer Chemother Pharmacol. 2016 Apr;77(4):787-95 PMID: 26931343
  266. Graded Foxo1 activity in Treg cells differentiates tumour immunity from spontaneous autoimmunity.
    Nature. 2016 Jan 28;529(7587):532-6 PMID: 26789248
  267. FOXO1 regulates L-Selectin and a network of human T cell homing molecules downstream of phosphatidylinositol 3-kinase.
    J Immunol. 2008 Sep 1;181(5):2980-9 PMID: 18713968
  268. Inhibition of the kinase ITK in a mouse model of asthma reduces cell death and fails to inhibit the inflammatory response.
    Sci Signal. 2015 Dec 01;8(405):ra122 PMID: 26628680
  269. Inhibiting PI3K reduces mammary tumor growth and induces hyperglycemia in a mouse model of insulin resistance and hyperinsulinemia.
    Oncogene. 2012 Jul 5;31(27):3213-22 PMID: 22037215
  270. Increased mammalian lifespan and a segmental and tissue-specific slowing of aging after genetic reduction of mTOR expression.
    Cell Rep. 2013 Sep 12;4(5):913-20 PMID: 23994476
  271. PI3K pathway dependencies in endometrioid endometrial cancer cell lines.
    Clin Cancer Res. 2013 Jul 1;19(13):3533-44 PMID: 23674493
  272. Asymmetric T lymphocyte division in the initiation of adaptive immune responses.
    Science. 2007 Mar 23;315(5819):1687-91 PMID: 17332376
  273. Single-Cell Phosphoproteomics Resolves Adaptive Signaling Dynamics and Informs Targeted Combination Therapy in Glioblastoma.
    Cancer Cell. 2016 Apr 11;29(4):563-573 PMID: 27070703
  274. Everolimus for angiomyolipoma associated with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis (EXIST-2): a multicentre, randomised, double-blind, placebo-controlled trial.
    Lancet. 2013 Mar 9;381(9869):817-24 PMID: 23312829
  275. The phosphoinositide 3-kinase pathway and therapy resistance in cancer.
    F1000Prime Rep. 2015 Feb 03;7:13 PMID: 25750731
  276. Divergent regulation of hepatic glucose and lipid metabolism by phosphoinositide 3-kinase via Akt and PKClambda/zeta.
    Cell Metab. 2006 May;3(5):343-53 PMID: 16679292
  277. First-in-Human Pharmacokinetic and Pharmacodynamic Study of the Dual m-TORC 1/2 Inhibitor AZD2014.
    Clin Cancer Res. 2015 Aug 1;21(15):3412-9 PMID: 25805799
  278. BAY 80-6946 is a highly selective intravenous PI3K inhibitor with potent p110α and p110δ activities in tumor cell lines and xenograft models.
    Mol Cancer Ther. 2013 Nov;12(11):2319-30 PMID: 24170767
  279. Inhibition of class IA PI3K enzymes in non-small cell lung cancer cells uncovers functional compensation among isoforms.
    Cancer Biol Ther. 2015 ;16(9):1341-52 PMID: 26176612
  280. Interplay between FOXO, TOR, and Akt.
    Biochim Biophys Acta. 2011 Nov;1813(11):1965-70 PMID: 21440577
  281. The hVps34-SGK3 pathway alleviates sustained PI3K/Akt inhibition by stimulating mTORC1 and tumour growth.
    EMBO J. 2016 Sep 1;35(17 ):1902-22 PMID: 27481935
  282. The clinical effect of the dual-targeting strategy involving PI3K/AKT/mTOR and RAS/MEK/ERK pathways in patients with advanced cancer.
    Clin Cancer Res. 2012 Apr 15;18(8):2316-25 PMID: 22261800
  283. Sirolimus for angiomyolipoma in tuberous sclerosis complex or lymphangioleiomyomatosis.
    N Engl J Med. 2008 Jan 10;358(2):140-51 PMID: 18184959
  284. Gsk3 is a metabolic checkpoint regulator in B cells.
    Nat Immunol. 2017 Mar;18(3):303-312 PMID: 28114292
Article Info
Journal
Cell
Abbr.
Cell
ISSN
1097-4172
DOI
10.1016/j.cell.2017.07.029
Email
[email protected]
Published
2017-08-10
Pages
605-635
Language
English
Region
United States
NLM ID
0413066
PMCID
PMC5726441
Subset
IM
Grants
NIAID NIH HHS · R21 AI124146 · United States
NCI NIH HHS · U54 CA210184 · United States
NIGMS NIH HHS · R37 GM041890 · United States
NIGMS NIH HHS · R01 GM041890 · United States
NCI NIH HHS · R35 CA197588 · United States
NCI NIH HHS · R01 CA158383 · United States
External Links
PubMed source DOI: 10.1016/j.cell.2017.07.029 PMC Full Text View journal details
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