PI3Kδ Pathway Dysregulation and Unique Features of Its Inhibition by Leniolisib in Activated PI3Kδ Syndrome and Beyond

Abstract

The phosphoinositide 3-kinase (PI3K) pathway regulates diverse cellular processes, with finely tuned PI3Kδ activity being crucial for immune cell development and function. Genetic hyperactivation of PI3Kδ causes the inborn error of immunity activated phosphoinositide 3-kinase δ syndrome (APDS). Several PI3Kδ inhibitors have been investigated as treatment options for APDS, but only leniolisib has shown both efficacy and tolerability. In contrast, severe immune-mediated adverse events such as colitis, neutropenia, and hepatotoxicity have been observed with other PI3Kδ inhibitors, particularly those indicated for hematological malignancies. We propose that leniolisib is distinguished from other PI3Kδ inhibitors due to its structure, specific inhibitory properties selectively targeting the δ isoform without overinhibition of the δ or γ isoforms, and the precise match between APDS mechanism of disease and drug mechanism of action. The phosphoinositide 3-kinase (PI3K) pathway regulates diverse cellular processes, with finely tuned PI3Kδ activity being crucial for immune cell development and function. Genetic hyperactivation of PI3Kδ causes the inborn error of immunity activated phosphoinositide 3-kinase δ syndrome (APDS). Several PI3Kδ inhibitors have been investigated as treatment options for APDS, but only leniolisib has shown both efficacy and tolerability. In contrast, severe immune-mediated adverse events such as colitis, neutropenia, and hepatotoxicity have been observed with other PI3Kδ inhibitors, particularly those indicated for hematological malignancies. We propose that leniolisib is distinguished from other PI3Kδ inhibitors due to its structure, specific inhibitory properties selectively targeting the δ isoform without overinhibition of the δ or γ isoforms, and the precise match between APDS mechanism of disease and drug mechanism of action. Cell growth, proliferation, survival, motility, differentiation, and metabolism are affected by intracellular signaling cascades often involving AKT, forkhead box O (FOXO), glycogen synthase kinase-3 (GSK3), and mechanistic (or mammalian) target of rapamycin (mTOR).1Fruman D.A. Chiu H. Hopkins B.D. Bagrodia S. Cantley L.C. Abraham R.T. The PI3K pathway in human disease.Cell. 2017; 170: 605-635Abstract Full Text Full Text PDF PubMed Scopus (1494) Google Scholar,2Gold M.R. Scheid M.P. Santos L. Dang-Lawson M. Roth R.A. Matsuuchi L. et al.The B cell antigen receptor activates the Akt (protein kinase B)/glycogen synthase kinase-3 signaling pathway via phosphatidylinositol 3-kinase.J Immunol. 1999; 163: 1894-1905Crossref PubMed Google Scholar These cascades can be initiated by the phosphorylation of membrane lipid phosphatidylinositol 4,5-bisphosphate (PIP2) to generate phosphatidylinositol 3,4,5-trisphosphate.3Okkenhaug K. Signaling by the phosphoinositide 3-kinase family in immune cells.Annu Rev Immunol. 2013; 31: 675-704Crossref PubMed Scopus (317) Google Scholar This reaction—and control of the associated intracellular signaling cascades—is regulated by class I phosphoinositide 3-kinases (PI3Ks).3Okkenhaug K. Signaling by the phosphoinositide 3-kinase family in immune cells.Annu Rev Immunol. 2013; 31: 675-704Crossref PubMed Scopus (317) Google Scholar These PI3Ks are heterodimers comprising distinct catalytic and regulatory subunits.1Fruman D.A. Chiu H. Hopkins B.D. Bagrodia S. Cantley L.C. Abraham R.T. The PI3K pathway in human disease.Cell. 2017; 170: 605-635Abstract Full Text Full Text PDF PubMed Scopus (1494) Google Scholar The most-studied regulatory subunit, p85α, is encoded by PIK3R1 and maintains inhibitory contacts with the catalytic subunit. These contacts regulate stability and recruitment of the catalytic subunit to membrane-associated phosphoproteins that relieve its inhibitory activity and position the catalytic subunit near PIP2.1Fruman D.A. Chiu H. Hopkins B.D. Bagrodia S. Cantley L.C. Abraham R.T. The PI3K pathway in human disease.Cell. 2017; 170: 605-635Abstract Full Text Full Text PDF PubMed Scopus (1494) Google Scholar,3Okkenhaug K. Signaling by the phosphoinositide 3-kinase family in immune cells.Annu Rev Immunol. 2013; 31: 675-704Crossref PubMed Scopus (317) Google Scholar The p110 catalytic subunit has 4 isoforms, α, β, γ, and δ, encoded by PIK3CA, PIK3CB, PIK3CG, and PIK3CD, respectively.3Okkenhaug K. Signaling by the phosphoinositide 3-kinase family in immune cells.Annu Rev Immunol. 2013; 31: 675-704Crossref PubMed Scopus (317) Google Scholar The γ subunit is unique among the class I PI3Ks by binding alternative regulatory subunits.1Fruman D.A. Chiu H. Hopkins B.D. Bagrodia S. Cantley L.C. Abraham R.T. The PI3K pathway in human disease.Cell. 2017; 170: 605-635Abstract Full Text Full Text PDF PubMed Scopus (1494) Google Scholar The α and β isoforms are expressed ubiquitously; γ and δ isoforms, mainly in immune cells.1Fruman D.A. Chiu H. Hopkins B.D. Bagrodia S. Cantley L.C. Abraham R.T. The PI3K pathway in human disease.Cell. 2017; 170: 605-635Abstract Full Text Full Text PDF PubMed Scopus (1494) Google Scholar,4Chantry D. Vojtek A. Kashishian A. Holtzman D.A. Wood C. Gray P.W. et al.p110delta, a novel phosphatidylinositol 3-kinase catalytic subunit that associates with p85 and is expressed predominantly in leukocytes.J Biol Chem. 1997; 272: 19236-19241Abstract Full Text Full Text PDF PubMed Scopus (218) Google Scholar The γ isoform is primarily involved with innate immunity; the δ isoform, with adaptive immunity, albeit with overlap.1Fruman D.A. Chiu H. Hopkins B.D. Bagrodia S. Cantley L.C. Abraham R.T. The PI3K pathway in human disease.Cell. 2017; 170: 605-635Abstract Full Text Full Text PDF PubMed Scopus (1494) Google Scholar B- and T-lymphocyte development and function are regulated partly by the degree of PI3Kδ activity.3Okkenhaug K. Signaling by the phosphoinositide 3-kinase family in immune cells.Annu Rev Immunol. 2013; 31: 675-704Crossref PubMed Scopus (317) Google Scholar Activity must be dynamically regulated to permit FOXO-dependent transcription and periods of mTOR signaling.3Okkenhaug K. Signaling by the phosphoinositide 3-kinase family in immune cells.Annu Rev Immunol. 2013; 31: 675-704Crossref PubMed Scopus (317) Google Scholar Therefore, homeostatic control of PI3Kδ activity is vital for immune health (Figure 1, A). The PI3Kδ is also expressed at low levels in other cell types, in which its expression can be further induced by specific stimuli. The PI3Kδ is expressed in the central nervous system, where it may be involved with axon regeneration.10Coulter T.I. Chandra A. Bacon C.M. Babar J. Curtis J. Screaton N. et al.Clinical spectrum and features of activated phosphoinositide 3-kinase δ syndrome: a large patient cohort study.J Allergy Clin Immunol. 2017; 139: 597-606.e4Abstract Full Text Full Text PDF PubMed Scopus (307) Google Scholar,16Fujita A. Kan O.K. Tonai K. Yamamoto N. Ogawa T. Fukuyama S. et al.Inhibition of PI3Kδ enhances poly I:C-induced antiviral responses and inhibits replication of human metapneumovirus in murine lungs and human bronchial epithelial cells.Front Immunol. 2020; 11: 432Crossref PubMed Scopus (11) Google Scholar Low levels of PI3Kδ are found in fibroblast-like synoviocytes, with increased expression in synovium of patients with rheumatoid arthritis.12Bartok B. Boyle D.L. Liu Y. Ren P. Ball S.T. Bugbee W.D. et al.PI3 kinase δ is a key regulator of synoviocyte function in rheumatoid arthritis.Am J Pathol. 2012; 180: 1906-1916Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar Tumor necrosis factor α with glucose can induce further expression of PI3Kδ in endothelial cells, where basal levels are low.13Whitehead M.A. Bombardieri M. Pitzalis C. Vanhaesebroeck B. Isoform-selective induction of human p110δ PI3K expression by TNFα: identification of a new and inducible PIK3CD promoter.Biochem J. 2012; 443: 857-867Crossref PubMed Scopus (44) Google Scholar,17Angulo I. Vadas O. Garçon F. Banham-Hall E. Plagnol V. Leahy T.R. et al.Phosphoinositide 3-kinase δ gene mutation predisposes to respiratory infection and airway damage.Science. 2013; 342: 866-871Crossref PubMed Scopus (462) Google Scholar In the lungs, PI3Kδ is expressed in fibroblasts and bronchial epithelial cells.18Deau M.C. Heurtier L. Frange P. Suarez F. Bole-Feysot C. Nitschke P. et al.A human immunodeficiency caused by mutations in the PIK3R1 gene.J Clin Invest. 2014; 124: 3923-3928Crossref PubMed Scopus (189) Google Scholar,19Dornan G.L. Siempelkamp B.D. Jenkins M.L. Vadas O. Lucas C.L. Burke J.E. Conformational of PI3Kδ by immunodeficiency mutations in PIK3CD and A. 2017; PubMed Scopus Google Scholar The PI3Kδ hyperactivation from in PIK3CD or in PIK3R1 causes the inborn error of immunity activated PI3Kδ syndrome in T.I. Chandra A. Bacon C.M. Babar J. Curtis J. Screaton N. et al.Clinical spectrum and features of activated phosphoinositide 3-kinase δ syndrome: a large patient cohort study.J Allergy Clin Immunol. 2017; 139: 597-606.e4Abstract Full Text Full Text PDF PubMed Scopus (307) Google B. J. et 3-kinase enhances to axon in the 2020; PubMed Scopus Google Y. G.L. Siempelkamp B.D. Jenkins M.L. et PIK3CD mutations of p110δ activated PI3Kδ syndrome in Allergy Clin Immunol. 2017; Full Text Full Text PDF PubMed Scopus Google L. mechanism for increased cell development in activated PI3K Immunol. PubMed Scopus Google Scholar in or p110δ that the inhibitory contacts between the or in p110δ that kinase activity or increased with the membrane and to PI3Kδ C.L. F. J.E. et mutations in the gene the catalytic subunit p110δ in cell and human Immunol. 2014; PubMed Scopus Google C.L. Y. A. Y. J. J. et mutation in PIK3R1 causes human immunodeficiency with due to of 2014; PubMed Scopus Google L. mechanism for increased cell development in activated PI3K Immunol. PubMed Scopus Google PI3K pathway to immunodeficiency and immune Allergy Clin Immunol. Full Text Full Text PDF PubMed Scopus Google S. J. and signaling in activated PI3K syndrome: from immunodeficiency to PubMed Scopus Google J. E. C. and of activated phosphoinositide 3-kinase δ syndrome from the Allergy Clin Full Text Full Text PDF PubMed Scopus Google Scholar PI3Kδ causes or of in and mTOR (Figure 1, S. J. and signaling in activated PI3K syndrome: from immunodeficiency to PubMed Scopus Google Scholar can be by increased phosphorylation of or C.L. F. J.E. et mutations in the gene the catalytic subunit p110δ in cell and human Immunol. 2014; PubMed Scopus Google Scholar The of APDS is often associated with severe due to of B- and development and both immune and T.I. Chandra A. Bacon C.M. Babar J. Curtis J. Screaton N. et al.Clinical spectrum and features of activated phosphoinositide 3-kinase δ syndrome: a large patient cohort study.J Allergy Clin Immunol. 2017; 139: 597-606.e4Abstract Full Text Full Text PDF PubMed Scopus (307) Google B. J. et 3-kinase enhances to axon in the 2020; PubMed Scopus Google E. M. E. E. F. M. et al.Inhibition of PI3K the and of human fibroblasts the of class I PubMed Scopus Google S. Genetic in phosphoinositide 3-kinase δ cell survival, differentiation, and Immunol. PubMed Scopus Google Lucas C.L. in activated PI3Kδ syndrome Immunol. Scopus Google in the activated Immunol. PubMed Scopus Google Chandra A. K. V. J. et development of B that infection in PubMed Scopus Google Scholar often may be and for T.I. Chandra A. Bacon C.M. Babar J. Curtis J. Screaton N. et al.Clinical spectrum and features of activated phosphoinositide 3-kinase δ syndrome: a large patient cohort study.J Allergy Clin Immunol. 2017; 139: 597-606.e4Abstract Full Text Full Text PDF PubMed Scopus (307) Google E. M. E. E. F. M. et al.Inhibition of PI3K the and of human fibroblasts the of class I PubMed Scopus Google Lucas C.L. in activated PI3Kδ syndrome Immunol. Scopus Google E. B. J. K. A. Heurtier L. et al.Clinical and associated with activated phosphoinositide 3-kinase δ syndrome a cohort study.J Allergy Clin Immunol. Full Text Full Text PDF PubMed Scopus Google M. S. M. P. F. et and features in patients with activated PI3Kδ syndrome a Rev Allergy Immunol. 2020; PubMed Scopus Google Scholar In contrast, levels of and B are often with in T.I. Chandra A. Bacon C.M. Babar J. Curtis J. Screaton N. et al.Clinical spectrum and features of activated phosphoinositide 3-kinase δ syndrome: a large patient cohort study.J Allergy Clin Immunol. 2017; 139: 597-606.e4Abstract Full Text Full Text PDF PubMed Scopus (307) Google E. M. E. E. F. M. et al.Inhibition of PI3K the and of human fibroblasts the of class I PubMed Scopus Google Lucas C.L. in activated PI3Kδ syndrome Immunol. Scopus Google E. B. J. K. A. Heurtier L. et al.Clinical and associated with activated phosphoinositide 3-kinase δ syndrome a cohort study.J Allergy Clin Immunol. Full Text Full Text PDF PubMed Scopus Google M. S. M. P. F. et and features in patients with activated PI3Kδ syndrome a Rev Allergy Immunol. 2020; PubMed Scopus Google Scholar PI3Kδ signaling also cell levels are often increased in patients with APDS low and specific T.I. Chandra A. Bacon C.M. Babar J. Curtis J. Screaton N. et al.Clinical spectrum and features of activated phosphoinositide 3-kinase δ syndrome: a large patient cohort study.J Allergy Clin Immunol. 2017; 139: 597-606.e4Abstract Full Text Full Text PDF PubMed Scopus (307) Google E. M. E. E. F. M. et al.Inhibition of PI3K the and of human fibroblasts the of class I PubMed Scopus Google Lucas C.L. in activated PI3Kδ syndrome Immunol. Scopus Google E. B. J. K. A. Heurtier L. et al.Clinical and associated with activated phosphoinositide 3-kinase δ syndrome a cohort study.J Allergy Clin Immunol. Full Text Full Text PDF PubMed Scopus Google M. S. M. P. F. et and features in patients with activated PI3Kδ syndrome a Rev Allergy Immunol. 2020; PubMed Scopus Google M. A. T. V. A. of activated phosphoinositide 3-kinase syndrome in and PubMed Scopus Google Scholar The also a from cells, with and increased and at the of central T.I. Chandra A. Bacon C.M. Babar J. Curtis J. Screaton N. et al.Clinical spectrum and features of activated phosphoinositide 3-kinase δ syndrome: a large patient cohort study.J Allergy Clin Immunol. 2017; 139: 597-606.e4Abstract Full Text Full Text PDF PubMed Scopus (307) Google B. J. et 3-kinase enhances to axon in the 2020; PubMed Scopus Google E. M. E. E. F. M. et al.Inhibition of PI3K the and of human fibroblasts the of class I PubMed Scopus Google Lucas C.L. in activated PI3Kδ syndrome Immunol. Scopus Google E. B. J. K. A. Heurtier L. et al.Clinical and associated with activated phosphoinositide 3-kinase δ syndrome a cohort study.J Allergy Clin Immunol. Full Text Full Text PDF PubMed Scopus Google M. S. M. P. F. et and features in patients with activated PI3Kδ syndrome a Rev Allergy Immunol. 2020; PubMed Scopus Google S. J. et and to at the of central Full Text Full Text PDF PubMed Scopus Google Scholar These have of and generate responses to particularly and that can be severe and in and C.L. F. J.E. et mutations in the gene the catalytic subunit p110δ in cell and human Immunol. 2014; PubMed Scopus Google C.L. Y. A. Y. J. J. et mutation in PIK3R1 causes human immunodeficiency with due to of 2014; PubMed Scopus Google S. Genetic in phosphoinositide 3-kinase δ cell survival, differentiation, and Immunol. PubMed Scopus Google Lucas C.L. in activated PI3Kδ syndrome Immunol. Scopus Google in the activated Immunol. PubMed Scopus Google Scholar due to can further be by associated with increased levels of and cells, the with T.I. Chandra A. Bacon C.M. Babar J. Curtis J. Screaton N. et al.Clinical spectrum and features of activated phosphoinositide 3-kinase δ syndrome: a large patient cohort study.J Allergy Clin Immunol. 2017; 139: 597-606.e4Abstract Full Text Full Text PDF PubMed Scopus (307) Google E. M. E. E. F. M. et al.Inhibition of PI3K the and of human fibroblasts the of class I PubMed Scopus Google E. B. J. K. A. Heurtier L. et al.Clinical and associated with activated phosphoinositide 3-kinase δ syndrome a cohort study.J Allergy Clin Immunol. Full Text Full Text PDF PubMed Scopus Google Scholar B- and also to the and observed in H. H. S. et as a novel target in 2020; PubMed Scopus Google E. M. E. E. F. M. et al.Inhibition of PI3K the and of human fibroblasts the of class I PubMed Scopus Google Lucas C.L. in activated PI3Kδ syndrome Immunol. Scopus Google E. B. J. K. A. Heurtier L. et al.Clinical and associated with activated phosphoinositide 3-kinase δ syndrome a cohort study.J Allergy Clin Immunol. Full Text Full Text PDF PubMed Scopus Google M. S. M. P. F. et and features in patients with activated PI3Kδ syndrome a Rev Allergy Immunol. 2020; PubMed Scopus Google M. A. T. V. A. of activated phosphoinositide 3-kinase syndrome in and PubMed Scopus Google H. A. A. O. C. et and to rapamycin in activated phosphoinositide 3-kinase δ syndrome: the for δ Immunol. PubMed Scopus Google Scholar may the in to of or respiratory and B. Boyle D.L. Liu Y. Ren P. Ball S.T. Bugbee W.D. et al.PI3 kinase δ is a key regulator of synoviocyte function in rheumatoid arthritis.Am J Pathol. 2012; 180: 1906-1916Abstract Full Text Full Text PDF PubMed Scopus (92) Google E. M. E. E. F. M. et al.Inhibition of PI3K the and of human fibroblasts the of class I PubMed Scopus Google E. B. J. K. A. Heurtier L. et al.Clinical and associated with activated phosphoinositide 3-kinase δ syndrome a cohort study.J Allergy Clin Immunol. Full Text Full Text PDF PubMed Scopus Google Scholar particularly may be caused partly by levels of as as levels of B cells, as in patients with other immune regulatory immune and such as factor of activated B or 4 A. T. A. A. H. et mutations in PIK3CD B cell development and PubMed Scopus Google A. K. H. S. H. et PI3Kδ B cell and causes 2020; Google B. J.E. et in human with mutations in 2014; PubMed Scopus Google V. D. M. et and in factor subunit immunodeficiency Allergy Clin Immunol. 2017; 139: Full Text Full Text PDF PubMed Scopus Google Scholar In in a of APDS increased cell and levels of which may also to F. M. PIK3CD innate B cell B immune PubMed Google Scholar of APDS and of which may be due to PI3Kδ expression in H. H. S. et as a novel target in 2020; PubMed Scopus Google E. M. E. E. F. M. et al.Inhibition of PI3K the and of human fibroblasts the of class I PubMed Scopus Google E. B. J. K. A. Heurtier L. et al.Clinical and associated with activated phosphoinositide 3-kinase δ syndrome a cohort study.J Allergy Clin Immunol. Full Text Full Text PDF PubMed Scopus Google B. D. C. M. S. C. et infection and in APDS the of and Scopus Google D. S. T. et of cell for activated Allergy Clin Immunol. Full Text Full Text PDF PubMed Scopus Google Scholar The expression of may for the of to and in patients with PIK3R1 T.I. Chandra A. Bacon C.M. Babar J. Curtis J. Screaton N. et al.Clinical spectrum and features of activated phosphoinositide 3-kinase δ syndrome: a large patient cohort study.J Allergy Clin Immunol. 2017; 139: 597-606.e4Abstract Full Text Full Text PDF PubMed Scopus (307) Google E. B. J. K. A. Heurtier L. et al.Clinical and associated with activated phosphoinositide 3-kinase δ syndrome a cohort study.J Allergy Clin Immunol. Full Text Full Text PDF PubMed Scopus Google H. A. A. O. C. et and to rapamycin in activated phosphoinositide 3-kinase δ syndrome: the for δ Immunol. PubMed Scopus Google Scholar and have been as in patients with PIK3R1 T.I. Chandra A. Bacon C.M. Babar J. Curtis J. Screaton N. et al.Clinical spectrum and features of activated phosphoinositide 3-kinase δ syndrome: a large patient cohort study.J Allergy Clin Immunol. 2017; 139: 597-606.e4Abstract Full Text Full Text PDF PubMed Scopus (307) Google E. B. J. K. A. Heurtier L. et al.Clinical and associated with activated phosphoinositide 3-kinase δ syndrome a cohort study.J Allergy Clin Immunol. Full Text Full Text PDF PubMed Scopus Google H. A. A. O. C. et and to rapamycin in activated phosphoinositide 3-kinase δ syndrome: the for δ Immunol. PubMed Scopus Google Scholar has been of and of APDS has target disease the of is with and immune is with such as or mTOR T.I. Chandra A. Bacon C.M. Babar J. Curtis J. Screaton N. et al.Clinical spectrum and features of activated phosphoinositide 3-kinase δ syndrome: a large patient cohort study.J Allergy Clin Immunol. 2017; 139: 597-606.e4Abstract Full Text Full Text PDF PubMed Scopus (307) Google E. B. J. K. A. Heurtier L. et al.Clinical and associated with activated phosphoinositide 3-kinase δ syndrome a cohort study.J Allergy Clin Immunol. Full Text Full Text PDF PubMed Scopus Google H. A. A. O. C. et and to rapamycin in activated phosphoinositide 3-kinase δ syndrome: the for δ Immunol. 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