{"doi":"10.1016/j.jaip.2023.09.016","title":"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","journal":"The Journal of Allergy and Clinical Immunology In Practice","year":2023,"id":332927,"datarank":0.4887144807032224,"base_score":3.258096538021482,"endowment":3.258096538021482,"self_citation_contribution":0.4887144807032224,"citation_network_contribution":0.0,"self_endowment_contribution":0.4887144807032224,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":25,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9563,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":614687,"name":"Anita Chandra","orcid":"0000-0002-9061-879X","position":1,"is_corresponding":false},{"id":1060139,"name":"Ewen Munro","orcid":null,"position":2,"is_corresponding":false},{"id":280640,"name":"V. 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