MEK inhibition profoundly reprograms myogenic super enhancers in mutant-RAS driven Rhabdomyosarcoma. Homo sapiens

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: Genome-wide profiles for histone marks, DNase hypersensitivity, transcription factors in mutant-RAS driven, Fusion-Negative Rhabdomyosarcoma (FN-RMS) cell lines and tissues