Molecular targeting of the meningioma cell signaling circuit reveals drug vulnerabilities including synergy between sulforaphane and focal adhesion kinase inhibition.

Abstract

Background: Meningiomas represent a common type of brain tumours and arise from the arachnoid cap cells which line the dural coverings of the brain. These predominantly benign tumours cause strong morbidity due to their intracranial location. Due to a lack of established pharmacological treatment approaches, surgery and radiotherapy remain the standard in clinical management of these tumours.

Methods: Here, we created a primary meningioma cell culture model and tested molecular compounds targeting key tumour-driving signalling pathways using cell viability assays and isobologram analysis.

Results: We found significant drug vulnerabilities within the meningioma-driving cell signalling network. Effective drugs included metformin, inhibitors of STAT3 and focal adhesion kinase (FAK), and the anti-inflammatory phytochemical sulforaphane, known as NRF2 pathway inducer and NFκB pathway inhibitor. Interestingly, FAK inhibitor Y15 and sulforaphane showed synergistic activity across cells of distinct meningioma patients, indicating this combination as a potential therapy approach.

Conclusions: Overall, we present a molecular targeting strategy for meningiomas that could pave the way for less invasive clinical management of these tumours and, as a result, help reduce patient mortality and morbidity. Metformin and sulforaphane both have FDA and EU pharmaceutical approval and thus could be repurposed promptly to establish a new meningioma therapy regimen.