USP10/GSK3β-mediated inhibition of PTEN drives resistance to PI3K inhibitors in breast cancer

Abstract

Breast cancer; Cell biology; Oncology

Cáncer de mama; Biología celular; Oncología

Càncer de mama; Biologia cel·lular; Oncologia

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.

Curtin Research fellowship, grant CRF130006, to MA. Raine Medical Research Foundation, Raine Priming grant, to MA. Australian government, Pawsey Supercomputing Center, National Computational Merit Allocation Scheme for computational resources (pa6/pawsey0196, pawsey0361). Harry Perkins Institute of Medical Research, MACA Cancer 200 Ride funds, to TW and JAN. Agency for Management of University and Research Grants to LM and VS. European Social Fund, grants 2019FI_B_01199 and 2021 SGR 01510, to LM and VS. Curtin University start-up fund, Cancer Council Western Australia, grant CCWA 2022/1165, to PJAE. WA Near-Miss Awards, WANMA2021/7, to PJAE. Worldwide Cancer Research Grant (24-0136) to PJAE. Oncology One to DK and PJAE.