UBE2C promotes leptomeningeal dissemination and is a therapeutic target in brain metastatic disease

Abstract

Background: Despite current improvements in systemic cancer treatment, brain metastases (BM) remain incurable, and there is an unmet clinical need for effective targeted therapies. Methods: Here, we sought common molecular events in brain metastatic disease. RNA sequencing of thirty human BM identified the upregulation of UBE2C, a gene that ensures the correct transition from metaphase to anaphase, across different primary tumor origins. Results: Tissue microarray analysis of an independent BM patient cohort revealed that high expression of UBE2C was associated with decreased survival. UBE2C-driven orthotopic mouse models developed extensive leptomeningeal dissemination, likely due to increased migration and invasion. Early cancer treatment with dactolisib (dual PI3K/mTOR inhibitor) prevented the development of UBE2C-induced leptomeningeal metastases. Conclusions: Our findings reveal UBE2C as a key player in the development of metastatic brain disease and highlight PI3K/mTOR inhibition as a promising anticancer therapy to prevent late-stage metastatic brain cancer.