Meningioma and schwannoma are common tumours of the nervous system that occur either sporadically or as part of NF2-related schwannomatosis (formerly neurofibromatosis type 2), a hereditary tumour predisposition syndrome. Despite their largely benign nature, recurrence rates approaching 50% and treatment options limited to surgery and radiotherapy highlight the urgent need for effective medical therapies and new therapeutic targets.

Our findings identify that the cellular prion protein (PrP^C) is consistently overexpressed in patient tissues and primary cells compared with normal controls and contributes to increased tumour cell proliferation, making it a novel therapeutic target in schwannoma¹ and meningioma tumours.

In both tumour types, PrP^C expression was driven by NFκB signalling, and pharmacological inhibition of NFκB using the clinically tested agent edasalonexent or the FDA-approved drug bortezomib significantly reduced proliferation in patient-derived 2D and 3D in vitro tumour models. Notably, these effects were observed at concentrations below those reported in the plasma of patients treated for other cancers.

Mechanistically, PrP^C promoted schwannoma¹ and meningioma cell survival and proliferation through interaction with the laminin receptor (LR/37/67 kDa) and activation of downstream AKT, FAK, and ERK signalling pathways. Disruption of the PrP^C–LR/37/67 kDa interaction effectively suppressed activation of these oncogenic pathways.

In addition, PrP^C knockdown significantly reduced the expression of multidrug resistance (MDR)-associated ABC transporters, MDR1 and MRP1, in patient-derived meningioma and schwannoma cells. PrP^C was expressed by both tumour cells and tumour-associated macrophages. Furthermore, radiation exposure increased PrP^C and MDR1 expression, suggesting that radiotherapy may promote multidrug resistance via PrP^C. Collectively, these results identify PrP^C as a central regulator of tumour signalling and drug resistance, making it a promising therapeutic target in sporadic and NF2-related meningiomas and schwannoma tumours.

Provenzano L, et al. Oncogene. 2017;36(44):61