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

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.

• Authors: Marielle E Yohe, Berkley E Gryder, Jack F Shern, Young K Song, Hsien-Chao Chou, Sivasish Sindiri, Arnulfo Mendoza, Rajesh Patidar, Xiaohu Zhang, Rajarashi Guha, Donna Butcher, Kristine A Isanogle, Christina M Robinson, Xiaoling Luo, Jin-Qiu Chen, Ashley Walton, Parirokh Awasthi, Elijah F Edmondson, Simone Difilippantonio, Jun S Wei, Keji Zhao, Marc Ferrer, Craig J Thomas, Javed Khan
• Journal: Science translational medicine (Sci Transl Med) Vol. 10 Issue 448 (07 04 2018) ISSN: 1946-6242 [Electronic] United States
• PMID: 29973406 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

Chemical References

• Chromatin
• Myogenin
• Oncogene Proteins, Fusion
• Protein Kinase Inhibitors
• Pyridones
• Pyrimidinones
• trametinib
• Receptor, IGF Type 1
• Extracellular Signal-Regulated MAP Kinases
• Mitogen-Activated Protein Kinase Kinases

Topics

• Animals
• Cell Differentiation
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Chromatin (metabolism)
• Enhancer Elements, Genetic (genetics)
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• Genes, ras
• Humans
• MAP Kinase Signaling System (drug effects)
• Mice
• Mitogen-Activated Protein Kinase Kinases (antagonists & inhibitors, metabolism)
• Muscle Development (drug effects, genetics)
• Myoblasts (metabolism, pathology)
• Myogenin (metabolism)
• Oncogene Proteins, Fusion (metabolism)
• Protein Kinase Inhibitors (pharmacology)
• Pyridones (pharmacology)
• Pyrimidinones (pharmacology)
• Receptor, IGF Type 1 (metabolism)
• Rhabdomyosarcoma (enzymology, genetics, pathology)
• Transcription, Genetic (drug effects)
• Xenograft Model Antitumor Assays