Bsci-04 targeting the pi3k-mtor pathway to treat ube2c-driven brain metastases

Abstract Brain metastases (BMs) are a devastating complication of advanced cancers associated with poor prognosis. Contrarily to the current improvement in systemic therapies, BMs are still incurable and one of the main causes of death in cancer patients. We analyzed BMs from thirty patients with various primary tumor origins by RNA sequencing and identified the upregulation of UBE2C, a gene involved in the correct transition from metaphase to anaphase. Using an independent cohort of patients with BMs, we demonstrated that high protein expression of UBE2C was associated with worse survival. UBE2C-driven cancer cells promoted migration and invasion in vitro and induced an aggressive phenotype and decreased survival in mouse orthotopic xenografts. PI3K/mTOR inhibition effectively blocked cancer cell signaling and prevented the development of leptomeningeal metastases. Therefore, we have identified UBE2C as a molecular marker of worse outcome in BMs patients and pre-clinically validated an effective therapy against UBE2C-driven brain metastatic disease.