MEK inhibition rewires enhancer landscapes in RAS-driven Rhabdomyosarcoma to unlock a myogenic differentation block

Trametinib-treated rhabdomyosarcoma cells undergo transcriptional reprogramming akin to myogenic differentiation. This reprogramming is induced by loss of ERK-mediated inhibition of MYOG expression. Restoration of MYOG allows establishment of super-enhancers at genes expressed by terminally differentiated myotubes. Our findings demonstrate that aberrant MAP kinase activity blocks differentiation in rhabdomyosarcoma and highlight trametinib as a potential therapeutic for RAS-mutated rhabdomyosarcoma. Overall design: RNA-seq in 2 FN-RMS cell lines exposed to either DMSO or Trametinib treatment for various concentrations and timepoints, and siRNA against MEK1 or scramble.