The PIK3CA gene mutation is the most frequently observed genetic abnormality in breast cancer, making it an attractive target for therapeutic intervention. While selective PI3K inhibitors have been approved for treating PIK3CA-mutant breast cancer, their efficacy has been limited due to a narrow therapeutic window and frequent treatment-related toxicities. Resistance to targeted therapies often occurs through the reactivation of the targeted signalling pathway. Likewise, recent evidence has linked loss-of-function mutations in the tumour suppressor PTEN in a small proportion of patients resistant to PI3K inhibitors. We demonstrate that PI3K inhibitors result in direct PTEN downregulation. This leads to continued PI3K signalling and tumour progression. These results undoubtedly explain why PI3K inhibitors frequently display such low levels of antitumour activity and indicate the reasoning behind the continuously low levels of target engagement by PI3K compounds in patients.
Mechanistically, PTEN acts as a homodimer to block PI3K signalling. However, PTEN can undergo phosphorylation by GSK3β in its C-terminal tail blocking PTEN dimerization and inhibiting the recruitment of PTEN to the membrane. We demonstrate that PI3K inhibitors de-repress GSK3β resulting in enzymatic inactivation of PTEN and consequently reactivation of PI3K signalling. Interestingly, we show that this process is mediated by USP10. Using both PI3K inhibitor resistant models and patient derived organoids we demonstrate that USP10 inhibition reactivates PTEN and re-sensitizes these tumours to PI3K inhibitors. The outcomes of our work provide a compelling rationale for advancing the development of USP10 inhibitors for the treatment of advanced breast cancer.