2025/11/14 by Shuang Tang, Qian Zhou, Johann S. Bergholz +19 · 1 voice
Biochemistry, Genetics and Molecular Biology · Neuroscience · #Axon Guidance and Neuronal Signaling #PI3K/AKT/mTOR signaling in cancer #Protein Tyrosine Phosphatases
paper · doi:10.1158/2159-8290.cd-25-1126
openalex created_date 2025/11/14 · openalex publication_date 2025/11/14 · openalex updated_date 2026/07/30
Loss of the tumor-suppressor PTEN drives cancer progression and therapeutic resistance, yet no targeted therapies exist for PTEN-deficient tumors. In this study, we identify a critical druggable mechanism in which PTEN loss induces PI3Kβ phosphorylation for tumorigenesis. Using the BioID interactome, we uncovered a 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, in which 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 wild-type 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. SIGNIFICANCE: We revealed a critical new mechanism that PTEN loss induces PI3Kβ phosphorylation and EPHA2/SRC/p-PI3KβY962 complex signaling to drive tumorigenesis. This work directs pharmaceutical development of p-PI3KβY962 inhibitors and biomarker-driven clinical trials repurposing dasatinib for PTEN-deficient solid tumor treatment, with potential to significantly improve outcomes of broad patients with PTEN-deficient tumors.