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Open Access Gold as soon as Publ. Version/Full Text is submitted to ZB.
USP10/GSK3B-mediated inhibition of PTEN drives resistance to PI3K inhibitors in breast cancer.
J. Clin. Invest., DOI: 10.1172/JCI180927:e180927 (2025)
Activating mutations in PIK3CA, the gene encoding the catalytic p110-alpha subunit of PI3K, are some of the most frequent genomic alterations in breast cancer. Alpelisib, a small-molecule inhibitor that targets p110-alpha, is a recommended drug for patients with PIK3CA-mutant advanced breast cancer. However, clinical success for PI3K inhibitors has been limited by their narrow therapeutic window. The lipid phosphatase PTEN is a potent tumour suppressor and a major negative regulator of the PI3K pathway. Unsurprisingly, inactivating mutations in PTEN correlate with tumour progression and resistance to PI3K inhibition due to persistent PI3K signalling. Here we demonstrate that PI3K inhibition leads rapidly to the inactivation of PTEN. Using a functional genetic screen we show that this effect is mediated by a USP10-GSK3-B signalling axis, in which USP10 stabilizes GSK3-B resulting in GSK3-B-mediated phosphorylation of the C-terminal tail of PTEN. This phosphorylation inhibits PTEN dimerization and thus prevents its activation. Downregulation of GSK3-B or USP10 re-sensitizes PI3K inhibitor resistant breast cancer models and patient derived organoids to PI3K inhibition and induces tumour regression. Our study establishes that enhancing PTEN activity is a new strategy to treat PIK3CA mutant tumours and provides a strong rationale for pursuing USP10 inhibitors in the clinic.
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Publication type
Article: Journal article
Document type
Scientific Article
Keywords
Breast Cancer ; Cell Biology ; Oncology ; Signal Transduction ; Ubiquitin-proteosome System
Language
english
Publication Year
2025
HGF-reported in Year
2025
ISSN (print) / ISBN
0021-9738
e-ISSN
1558-8238
Quellenangaben
Article Number: e180927
Publisher
American Society of Clinical Investigation
Reviewing status
Peer reviewed
Institute(s)
Institute of Lung Health and Immunity (LHI)
POF-Topic(s)
30202 - Environmental Health
Research field(s)
Lung Research
PSP Element(s)
G-501694-001
PubMed ID
40991650
Erfassungsdatum
2025-11-04