PI3KΓ: A KEY PLAYER IN CANCER SIGNALLING PATHWAYS AND THERAPEUTIC TARGET FOR CANCER TREATMENT

Phosphoinositide 3-kinase gamma (PI3Kγ) plays a vital role in cell signaling pathways essential for various physiological processes, including cell growth, differentiation, and survival. Dysregulation of PI3K signaling is implicated in the development and progression of several cancers. Activation of PI3K leads to the phosphorylation of critical proteins such as protein kinase B (PKB), ribosomal protein S6 kinase (RSK), and extracellular signal-regulated kinases 1 and 2 (ERK1/2), facilitated by the presence of phosphatidylinositol 3,4,5-triphosphate (PIP3). PI3K is involved in regulating immune responses, including thymocyte growth, neutrophil migration, and T cell activation. Numerous malignancies, including melanoma, lung cancer, prostate cancer, and breast cancer, have been linked to PI3K activity. For instance, PI3K activation is known to enhance breast cancer cell migration and invasion by stimulating the Akt/mTOR signaling pathway. Structurally, PI3Kγ consists of a catalytic subunit (P110γ) and regulatory subunits that modulate its activity. The P110γ domain architecture includes a C2 domain, helical domain, Ras-binding domain, and catalytic domain, which are critical for its function. The ATP binding pocket of P110γ is organized into distinct regions that influence substrate affinity and interactions, providing potential targets for inhibitor design.The PI3K pathway is activated through a multi-step process involving G protein-coupled receptors (GPCRs) and receptor tyrosine kinases (RTKs), resulting in the conversion of phosphatidylinositol (4,5)-bisphosphate (PIP2) to PIP3. This activation is tightly regulated by the phosphatase PTEN, which dephosphorylates PIP3 back to PIP2. PI3Kγ also influences cancer stem cell dynamics and immune modulation in the tumor microenvironment, presenting opportunities for novel therapeutic strategies.