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Sci Transl Med. 2018 Jul 4;10(448). pii: eaan4470. doi: 10.1126/scitranslmed.aan4470.

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

Author information

1
Oncogenomics Section, Genetics Branch, National Cancer Institute, National Institutes of Health (NIH), Bethesda, MD 20892, USA. yoheme@mail.nih.gov khanjav@mail.nih.gov.
2
Pediatric Oncology Branch, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
3
Oncogenomics Section, Genetics Branch, National Cancer Institute, National Institutes of Health (NIH), Bethesda, MD 20892, USA.
4
Division of Preclinical Innovation, National Center for Advancing Translational Sciences, NIH, Bethesda, MD 20892, USA.
5
Pathology/Histotechnology Laboratory, Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research, NIH, Frederick, MD 21702, USA.
6
Laboratory Animal Sciences Program, Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research, NIH, Frederick, MD 21701, USA.
7
Collaborative Protein Technology Resource, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
8
Systems Biology Center, National Heart Lung and Blood Institute, NIH, Bethesda, MD 20892, USA.

Abstract

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.

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