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Kumari, N.* ; Wright, S.C.* ; Witham, C.M.* ; Monserrat, L.* ; Palafox, M.* ; Charles Richard, J.L.* ; Costa, C.* ; Elkabets, M.* ; Agostino, M.* ; Klemm, T.* ; Eccles, M.K.* ; Garnham, A.* ; Wu, T.* ; Nilsson, J.A.* ; Walz, N.* ; Venugopal, V.* ; Cerra, A.* ; Vasilevski, N.* ; Bridgeman, S.C.* ; Bassi, S.* ; Saei, A.* ; Helal, M.* ; Neundorf, P.* ; Riedel, A.* ; Rosenfeldt, M.* ; Gill, J.* ; Pahor, N. ; Hartmann, O. ; Chung, J.* ; Sidhu, S.S.* ; Moderau, N.* ; Jha, S.* ; Rodon, J.* ; Diefenbacher, M. ; Komander, D.* ; Serra, V.* ; Eichhorn, P.*

USP10/GSK3B-mediated inhibition of PTEN drives resistance to PI3K inhibitors in breast cancer.

J. Clin. Invest., DOI: 10.1172/JCI180927:e180927 (2025)
Postprint DOI PMC
Open Access Gold möglich sobald Verlagsversion bei der ZB eingereicht worden ist.
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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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Breast Cancer ; Cell Biology ; Oncology ; Signal Transduction ; Ubiquitin-proteosome System
Sprache englisch
Veröffentlichungsjahr 2025
HGF-Berichtsjahr 2025
ISSN (print) / ISBN 0021-9738
e-ISSN 1558-8238
Zeitschrift Journal of Clinical Investigation
Quellenangaben Band: , Heft: , Seiten: , Artikelnummer: e180927 Supplement: ,
Verlag American Society of Clinical Investigation
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Lung Health and Immunity (LHI)
POF Topic(s) 30202 - Environmental Health
Forschungsfeld(er) Lung Research
PSP-Element(e) G-501694-001
DOI 10.1172/JCI180927
PubMed ID 40991650
Erfassungsdatum 2025-11-04
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