Malignant peripheral nerve sheath tumors often arise in patients with neurofibromatosis type 1 and are among the most treatment-refractory types of sarcoma. Overall survival in patients with relapsed disease remains poor, and thus novel therapeutic approaches are needed. NF1 is essential for negative regulation of RAS activity and is altered in about 90% of malignant peripheral nerve sheath tumors (MPNST). A complex interplay of upstream signaling and parallel RAS-driven pathways characterizes NF1-driven tumorigenesis, and inhibiting more than one RAS effector pathway is therefore necessary. To devise potential combination therapeutic strategies, we identified actionable alterations in signaling that underlie adaptive and acquired resistance to MEK inhibitor (MEKi). Using a series of proteomic, biochemical, and genetic approaches in an model of MEKi resistance provided a rationale for combination therapies. HGF/MET signaling was elevated in the MEKi-resistant model. HGF overexpression conferred resistance to MEKi in parental cells. Depletion of HGF or MET restored sensitivity of MEKi-resistant cells to MEKi. Finally, a combination of MEK and MET inhibition demonstrated activity in models of MPNST and may therefore be effective in patients with MPNST harboring genetic alterations in . SIGNIFICANCE: This study demonstrates that MEKi plus MET inhibitor may delay or prevent a novel mechanism of acquired MEKi resistance, with clinical implications for MPNST patients harboring alterations.