The mesenchymal state of NF1-associated malignant peripheral nerve sheath tumor is vulnerable to synergistic p53-pathway activation by combined MEK and MDM2 inhibition

Using genetically engineered mouse models, we show that Nf1 loss efficiently induced RAS-MEK-ERK/MAPK-driven PNFs from developmentally abnormal nonmyelinating SCs, but no SC/epithelial-to-mesenchymal transition (EMT) or MPNST.

Additional loss of Cdkn2a or p53 was required for Nf1-deficient PNFs to progress into MPNSTs. Using a high-throughput drug-repurposing screen and p53-off/on switchable system, we uncovered that MEK inhibition (MEKi) reduced Mdm2/MDM2 expression and activated p53-mediated apoptosis, which was curbed by the p53-MDM2 negative feedback loop, but overcome by MDM2 inhibitors (MDM2i). Importantly, combined MEKi/MDM2i treatment eliminated MEKi- and MDM2i-induced resistant MPNSTs by synergistically activating p53-mediated MEKi-induced apoptosis and MDM2i-driven EMT reversal with SC differentiation.