USP10/GSK3β-mediated inhibition of PTEN drives resistance to PI3K inhibitors in breast cancer
Activating mutations in PIK3CA, the gene encoding the catalytic p110α subunit of PI3K, are some of the most frequent genomic alterations in breast cancer. Alpelisib, a small-molecule inhibitor that targets p110α, is a recommended drug for patients with PIK3CA-mutant advanced breast cancer. However, clinical success for PI3K inhibitors (PI3Kis) has been limited by their narrow therapeutic window. The lipid phosphatase PTEN is a potent tumor suppressor and a major negative regulator of the PI3K pathway. Unsurprisingly, inactivating mutations in PTEN correlate with tumor progression and resistance to PI3K inhibition due to persistent PI3K signaling. 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-GSK3β signaling axis, in which USP10 stabilizes GSK3β, resulting in GSK3β-mediated phosphorylation of the C-terminal tail of PTEN. This phosphorylation inhibits PTEN dimerization and thus prevents its activation. Downregulation of GSK3β or USP10 resensitizes PI3Ki-resistant breast cancer models and patient-derived organoids to PI3K inhibition and induces tumor regression. Our study establishes that enhancing PTEN activity is a new strategy to treat PIK3CA mutant tumors and provides a strong rationale for pursuing USP10 inhibitors in the clinic.
Authors
- Natali Vasilevski (ORCID: https://orcid.org/0000-0002-6146-7937)
- Sudhakar Jha (ORCID: https://orcid.org/0000-0002-5093-4843)
- Oliver Hartmann (ORCID: https://orcid.org/0000-0002-5663-645X)
- Veena Venugopal (ORCID: https://orcid.org/0009-0008-9211-6962)
- John Lalith Charles Richard (ORCID: https://orcid.org/0000-0002-1186-6390)
- Laia Monserrat (ORCID: https://orcid.org/0000-0002-8802-3033)
- Azad Saei (ORCID: https://orcid.org/0000-0002-1000-2953)
- Melissa Eccles (ORCID: https://orcid.org/0000-0003-0853-7833)
- Marta Palafox (ORCID: https://orcid.org/0000-0002-1762-3250)
- Alexandra L. Garnham (ORCID: https://orcid.org/0000-0002-8312-8450)
- Mark Agostino (ORCID: https://orcid.org/0000-0002-1799-0392)
- Jespal Gill
- Angela Riedel (ORCID: https://orcid.org/0009-0006-9411-4210)
- Theresa Klemm (ORCID: https://orcid.org/0000-0002-2847-3550)
- Carlotta Costa (ORCID: https://orcid.org/0000-0002-1199-2485)
- Sachdev S. Sidhu (ORCID: https://orcid.org/0000-0001-7755-5918)
- Markus E. Diefenbacher (ORCID: https://orcid.org/0000-0002-7402-7949)
- Sonya Vivien Wright
- Nina Moderau (ORCID: https://orcid.org/0000-0001-5656-839X)
- Nikolett Pahor
- Jonas A. Nilsson (ORCID: https://orcid.org/0000-0003-0346-6837)
- Stephanie C. Bridgeman (ORCID: https://orcid.org/0000-0002-8399-5458)
- Moutaz Helal (ORCID: https://orcid.org/0000-0002-9561-1669)
- Pieter J.A. Eichhorn (ORCID: https://orcid.org/0000-0001-5840-943X)
- Violeta Serra (ORCID: https://orcid.org/0000-0001-6620-1065)
- Mathias T. Rosenfeldt (ORCID: https://orcid.org/0000-0001-7650-8458)
- Christopher M. Witham (ORCID: https://orcid.org/0000-0002-1626-6714)
- David Komander (ORCID: https://orcid.org/0000-0002-8092-4320)
- Nikita Walz (ORCID: https://orcid.org/0000-0002-5058-875X)
- Anthony Cerra (ORCID: https://orcid.org/0009-0002-8023-6445)
- Ting Wu (ORCID: https://orcid.org/0000-0003-2073-758X)
- Nishi Kumari (ORCID: https://orcid.org/0000-0003-4311-7578)
- Jacky Chung
- Jordi Rodon (ORCID: https://orcid.org/0000-0002-1032-9091)
- Philipp Neundorf
- Silvia Li Bassi
- Moshe Elkabets
Institutions
- Agency for Science, Technology and Research (SG)
- Oklahoma State University (US)
- Ben-Gurion University of the Negev (IL)
- The Royal Melbourne Hospital (AU)
- The University of Texas MD Anderson Cancer Center (US)
- Harvard University (US)
- University of Waterloo (CA)
- The University of Melbourne (AU)
- National University of Singapore (SG)
- Murdoch University (AU)
- The University of Western Australia (AU)
- Walter and Eliza Hall Institute of Medical Research (AU)
- Curtin University (AU)
- University of Würzburg (DE)
- Harry Perkins Institute of Medical Research (AU)
- Helmholtz Zentrum München (DE)
- Massachusetts General Hospital (US)
- National University Cancer Institute, Singapore (SG)
- Universitätsklinikum Würzburg (DE)
- German Center for Lung Research (DE)
- Vall d'Hebron Institute of Oncology (ES)
- Imperial College London (GB)
- Genome Institute of Singapore (SG)
- Ludwig-Maximilians-Universität München (DE)
Publication Details
- Journal
- Journal of Clinical Investigation
- Published
- 2025-09-23
- DOI
- https://doi.org/10.1172/jci180927
- Primary Topic
- PI3K/AKT/mTOR signaling in cancer
- Type
- article
- Field-Weighted Citation Impact
- 0.00