The two recently FDA-approved drugs for pNFs, the MEK inhibitors selumetinib and mirdametinib, are not used to prevent or treat MPNSTs.<h4>Methods</h4>The MEK inhibitor trametinib and the dual HDAC/PI3K inhibitor fimepinostat were assessed for growth inhibitory effects in nine unique patient-derived MPNST cell lines, as both drugs have preclinical efficacy in other Schwann cell-derived tumors.<h4>Results</h4>Trametinib, which is approved for malignant melanomas, promoted cell death in 7/9 MPNST cell lines with a geometric mean GI50 = 17 nM. Here, HDAC9 is linked to malignant peripheral nerve sheath tumor.