Subtoxic concentrations of the MEK inhibitor MEK162 and the PI3Kα-specific inhibitor BYL719 synergized to trigger apoptosis in <i>NRAS</i>-mutated RMS cells <i>in vitro</i> and <i>in vivo</i><i>NRAS</i>- or <i>HRAS</i>-mutated cell lines were more vulnerable to MEK162/BYL719 cotreatment than <i>RAS</i> wild-type cell lines, and MEK162/BYL719 cotreatment was more effective to trigger apoptosis in <i>NRAS</i>-mutated than <i>RAS</i> wild-type RMS tumors <i>in vivo</i> We identified BCL-2-modifying factor (BMF) as an inhibitory target of oncogenic NRAS, with either NRAS silencing or MEK inhibition upregulating BMF mRNA and protein levels, which BYL719 further increased.