USP10/GSK3beta-mediated inhibition of PTEN drives resistance to PI3K inhibitors in breast cancer

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

Author(s): Kumari, N; Richard, JL; Wright, SC; Eccles, M; Witham, CM; Bridgeman, S; Monserrat, L; Eichhorn, PJA; Palafox, M; Costa, C; Elkabets, M; Agostino, M; Klemm, T; Garnham, A; Wu, T; Nilsson, JA; Walz, N; Venugopal, V; Cerra, A; Vasilevski, N; Bassi, S; Saei, A; Helal, M; Neundorf, P; Riedel, A; Rosenfeldt, M; Gill, J; Pahor, N; Hartmann, O; Chung, J; Sidhu, SS; Moderau, N; Jha, S; Rodon, J; Diefenbacher, ME; Komander, D; Serra, V;
Journal Title: Journal of Clinical Investigation
Abstract: Activating mutations in PIK3CA, the gene encoding the catalytic p110alpha subunit of PI3K, are some of the most frequent genomic alterations in breast cancer. Alpelisib, a small-molecule inhibitor that targets p110alpha, 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-GSK3beta signaling axis, in which USP10 stabilizes GSK3beta, resulting in GSK3beta-mediated phosphorylation of the C-terminal tail of PTEN. This phosphorylation inhibits PTEN dimerization and thus prevents its activation. Downregulation of GSK3beta 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.
Publisher: ACI
Keywords: Humans; *PTEN Phosphohydrolase/metabolism/genetics/antagonists & inhibitors; *Breast Neoplasms/drug therapy/genetics/pathology/metabolism/enzymology; Female; *Drug Resistance, Neoplasm; *Glycogen Synthase Kinase 3 beta/metabolism/genetics; Animals; Mice; *Ubiquitin Thiolesterase/metabolism/genetics; *Phosphoinositide-3 Kinase Inhibitors/pharmacology; Cell Line, Tumor; Signal Transduction/drug effects; Class I Phosphatidylinositol 3-Kinases/genetics/metabolism/antagonists &; inhibitors; *Neoplasm Proteins/metabolism/genetics/antagonists & inhibitors; Phosphatidylinositol 3-Kinases/metabolism/genetics; Breast cancer; Cell biology; Oncology; Signal transduction; Ubiquitin-proteosome system
Research Division(s): New Medicines and Diagnostics; Bioinformatics and Computational Biology; Ubiquitin Signalling
PubMed ID: 40991650
Publisher's Version: https://doi.org/10.1172/JCI180927
Open Access at Publisher's Site: https://doi.org/10.1172/JCI180927
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2025-10-20 01:57:45

Last Modified: 2025-12-15 01:28:24