Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma (PIK3CG) (PIK3CG)

Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma (PIK3CG), also known as p110γ, is a Class IB phosphoinositide 3-kinase (PI3K) primarily expressed in hematopoietic cells such as macrophages, neutrophils, and T cells [1, 3, 9]. Unlike Class IA PI3Ks, which are typically activated by receptor tyrosine kinases, PIK3CG is uniquely activated by G protein-coupled receptors (GPCRs) through its association with regulatory subunits like p101 or p84/p87 [3, 4]. It functions by phosphorylating phosphatidylinositol 4,5-bisphosphate (PIP2) to generate the second messenger phosphatidylinositol 3,4,5-trisphosphate (PIP3), which recruits downstream effectors like AKT to the plasma membrane [1, 4]. This signaling pathway is a master regulator of immune cell functions, including chemotaxis, inflammatory cytokine production, and the respiratory burst [5, 9]. In oncology, PIK3CG is a key target because it promotes an immunosuppressive tumor microenvironment by driving the M2 polarization of tumor-associated macrophages; inhibiting this enzyme can reprogram the immune microenvironment to favor anti-tumor activity [2, 5, 9]. Beyond cancer, PIK3CG is implicated in inflammatory diseases like rheumatoid arthritis and COPD, as well as cardiovascular conditions [1, 7, 11]. Therapeutic strategies include selective small-molecule inhibitors like eganelisib and dual PI3Kγ/δ inhibitors like duvelisib, which are being evaluated for their ability to enhance the efficacy of checkpoint inhibitors and treat various malignancies [5, 6, 7].

Other names

PI3K-gammap110-gammaPI3CGp120-PI3KIMD97Phosphoinositide-3-kinase catalytic gamma polypeptide

Inhibition of the catalytic activity of the p110γ subunit of Class IB phosphoinositide 3-kinase, preventing the phosphorylation of phosphatidylinositol 4,5-bisphosphate (PIP2) to phosphatidylinositol 3,4,5-trisphosphate (PIP3) [1, 4, 5]. This disruption blocks downstream AKT/mTOR signaling and modulates immune cell recruitment, specifically promoting the polarization of tumor-associated macrophages from an immunosuppressive M2-like phenotype to a pro-inflammatory M1-like phenotype [5, 9].