Research ArticleCancer

MEK inhibition induces MYOG and remodels super-enhancers in RAS-driven rhabdomyosarcoma

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Science Translational Medicine  04 Jul 2018:
Vol. 10, Issue 448, eaan4470
DOI: 10.1126/scitranslmed.aan4470

Muscling in on RAS

Rhabdomyosarcomas occur when skeletal muscle precursors fail to differentiate. These tumors often display mutated RAS, although the mechanism through which RAS promotes tumor formation has remained unclear. Yohe et al. discovered that RAS blocks myogenesis in fusion-negative rhabdomyosarcoma (FN-RMS) by inducing epigenetic changes via the MAP kinase pathway. Treatment with the MEK/ERK inhibitor trametinib led to chromatin and super-enhancer remodeling, which in turn resulted in cellular differentiation in cell lines and improved tumor volume and survival in xenograft mouse models. Combining trametinib and an IGF1R inhibitor synergistically improved treatment efficacy in the xenografted mice.

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