ArticleCancer discovery2026
PTEN Loss Promotes PI3Kβ Phosphorylation and EPHA2/SRC/p-PI3KβY962 Complex Assembly to Drive Tumorigenesis.
Article in Cancer discovery, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 5 papers.
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Who cites it
5 citing papers in PubMed.
- Pseudorabies virus pUL40 drives inflammatory signaling through competitive hijacking of EphA2 from the Akt-EphA2 interaction.Veterinary research · 2026Article
- LL-37 inhibits osteosarcoma progression by suppressing SQLE-mediated cholesterol synthesis via the PTEN/AKT/mTOR pathway.Journal of bone oncology · 2026Article
- EphA2 as an oncogenic driver: roles and mechanisms of action in cancer.Molecular biology reports · 2026Review
- Poricoic Acid A Attenuates Osteoarthritis Progression by Stabilizing PTEN and Suppressing PI3K/AKT Signaling.International journal of molecular sciences · 2026Article
- Macrophage-based therapeutic strategies in glioblastoma: advancements in drug delivery and immunotherapy.Frontiers in oncology · 2026Review
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Authors and funding
22 authors.
Funding
Abstract
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.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.