PI3K6 Pathway Dysregulation and Unique Features of Its Inhibition by Leniolisib in Activated PI3K6 Syndrome and Beyond

The phosphoinositide 3-kinase (PI3K) pathway regulates diverse cellular processes, with finely tuned PI3K6 activity being crucial for immune cell development and function. Genetic hyperactivation of PI3K6 causes the inborn error of immunity activated phosphoinositide 3-kinase 6 syndrome (APDS). Several PI3K6 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 PI3K6 inhibitors, particularly those indicated for hematological malignancies. We propose that leniolisib is distinguished from other PI3K6 inhibitors due to its structure, specific inhibitory properties selectively targeting the 6 isoform without overinhibition of the 6 or y isoforms, and the precise match between APDS mechanism of disease and drug mechanism of action. (c) 2023 The Authors. Published by Elsevier Inc. on behalf of the American Academy of Allergy, Asthma & Immunology. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). (J Allergy Clin Immunol Pract 2024;12:69-78)