PTEN Loss Promotes PI3K
Menée à l'aide de lignées cellulaires et de xénogreffes sur des modèles murins, cette étude met en évidence un mécanisme par lequel l'absence d'expression du suppresseur de tumeur PTEN induit la tumorigenèse en favorisant la phosphorylation de la kinase PI3Kbêta et l'assemblage du complexe EPHA2/SRC/p-PI3Kbêta
Loss of tumor suppressor PTEN drives cancer progression and therapeutic resistance, yet no targeted therapies exist for PTEN-deficient tumors. Here, we identify a critical druggable mechanism where PTEN-loss induces PI3Kβ phosphorylation for tumorigenesis. Using BioID interactome, we uncovered phosphorylation-dependent PI3Kβ–EPHA2 interaction in PTEN-null cells, driven by p-PI3KβY962. PTEN functions as a tyrosine phosphatase that normally dephosphorylates p-PI3KβY962. In PTEN-deficient contexts, enhanced p-PI3KβY962 forms a complex with EPHA2 and SRC, where both kinases contribute to PI3Kβ phosphorylation, activating oncogenic pERK/c-MYC and pAKT pathways. We developed a selective p-PI3KβY962 antibody detecting p-PI3KβY962 in PTEN-deficient tumors across preclinical models and clinical tumor specimens. Disrupting p-PI3KβY962 suppressed tumor growth in multiple PTEN-null models. Dasatinib, an FDA-approved SRC/EPHA2 inhibitor, effectively reduced p-PI3KβY962 and inhibited tumor progression in PTEN-null but not PTEN-WT tumors. These findings establish p-PI3KβY962 as a druggable target and biomarker for developing targeted therapy in PTEN-deficient cancers beyond conventional PI3K kinase inhibition.
Cancer Discovery , article en libre accès, 2025