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

MEK inhibition decreases cell viability and induces differentiation in RAS-driven rhabdomyosarcoma via an epigenetic mechanism. 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. The RAS isoforms are frequently mutated in many types of human cancers, including PAX3/PAX7 fusion-negative rhabdomyosarcoma. Pediatric RMS arises from skeletal muscle progenitor cells that have failed to differentiate normally. The role of mutant RAS in this differentiation blockade is incompletely understood. We demonstrate that oncogenic RAS, acting through the RAF–MEK [mitogen-activated protein kinase (MAPK) kinase]–ERK (extracellular signal–regulated kinase) MAPK effector pathway, inhibits myogenic differentiation in rhabdomyosarcoma by repressing the expression of the prodifferentiation myogenic transcription factor, MYOG. This repression is mediated by ERK2-dependent promoter-proximal stalling of RNA polymerase II at the MYOG locus. Small-molecule screening with a library of mechanistically defined inhibitors showed that RAS-driven RMS is vulnerable to MEK inhibition. MEK inhibition with trametinib leads to the loss of ERK2 at the MYOG promoter and releases the transcriptional stalling of MYOG expression. MYOG subsequently opens chromatin and establishes super-enhancers at genes required for late myogenic differentiation. Furthermore, trametinib, in combination with an inhibitor of IGF1R, potently decreases rhabdomyosarcoma cell viability and slows tumor growth in xenograft models. Therefore, this combination represents a potential therapeutic for RAS-mutated rhabdomyosarcoma.