Malignant peripheral nerve sheath tumors (MPNST) are aggressive soft tissue sarcomas that have a propensity to occur in individuals with neurofibromatosis type 1. Biallelic NF1 alteration is nearly universally found in MPNST and its loss disrupts negative regulation of RAS activity in these cancer cells. By interrogation of kinome activity through an unbiased screen and targeted evaluation of the signaling response to MEK inhibition, Wang and colleagues have identified global activation of upstream receptor tyrosine kinases (RTK), converging on activation of RAS, as a mechanism limiting the sensitivity to MEK inhibition. An inhibitor of the protein tyrosine phosphatase SHP2, a critical mediator of RAS signal transduction downstream of multiple RTK, given in combination with MEK inhibitor, represents a potential therapeutic strategy to overcome the loss-of-feedback–associated upstream activation. The combination is effective in preclinical models of MPNST. For details, see article by Wang and colleagues on page 5367.