Here, we provide extensive evidence showing the preclinical anti-proliferative and anti-tumor activity of LXH254 plus trametinib, through more durable inhibition of ERK pathway, relative to either single agent, in a large panel of traditional and patient-derived models of NF1-MPNST, in vitro and in vivo, as well as in MEKi-resistant models driven by upregulation of RTK activity. Here, NF1 is linked to malignant peripheral nerve sheath tumor.