Related Experiment Video

Updated: Feb 8, 2026

Tumorsphere Derivation and Treatment from Primary Tumor Cells Isolated from Mouse Rhabdomyosarcomas
09:21

Tumorsphere Derivation and Treatment from Primary Tumor Cells Isolated from Mouse Rhabdomyosarcomas

Published on: September 13, 2019

7.6K

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

Marielle E Yohe1,2, Berkley E Gryder3, Jack F Shern2

  • 1Oncogenomics Section, Genetics Branch, National Cancer Institute, National Institutes of Health (NIH), Bethesda, MD 20892, USA. yoheme@mail.nih.gov khanjav@mail.nih.gov.

Science Translational Medicine
|July 6, 2018
PubMed

Insights

Oncogenic RAS mutations block muscle cell differentiation in rhabdomyosarcoma by inhibiting MYOG expression. MEK inhibitor trametinib restores MYOG, offering a potential therapy for RAS-mutated rhabdomyosarcoma.

Area of Science:

  • Molecular biology
  • Cancer research
  • Cell differentiation

Background:

  • RAS isoforms are frequently mutated in human cancers, including rhabdomyosarcoma (RMS).
  • Mutant RAS contributes to impaired skeletal muscle progenitor cell differentiation in pediatric RMS, but the mechanism is unclear.

Purpose of the Study:

  • To elucidate the mechanism by which mutant RAS inhibits myogenic differentiation in RMS.
  • To identify potential therapeutic strategies targeting RAS-driven RMS.

Main Methods:

  • Investigated the role of the RAF-MEK-ERK MAPK pathway in RAS-mediated differentiation blockade.
  • Utilized small-molecule screening to identify inhibitors effective against RAS-driven RMS.
  • Assessed the effects of MEK inhibition (trametinib) and combination therapy (trametinib + IGF1R inhibitor) in cell lines and xenograft models.

Main Results:

  • Oncogenic RAS, via the MAPK pathway, represses MYOG expression by causing RNA polymerase II stalling at the MYOG locus.
  • MEK inhibition with trametinib releases MYOG transcriptional stalling, leading to chromatin opening and super-enhancer establishment for myogenic genes.
  • Combination therapy with trametinib and an IGF1R inhibitor significantly reduced RMS cell viability and tumor growth in vivo.

Conclusions:

  • The RAF-MEK-ERK pathway and subsequent MYOG repression are key mechanisms in RAS-driven RMS differentiation blockade.
  • MEK inhibition is a promising therapeutic strategy for RAS-mutated RMS.
  • Combination therapy targeting MEK and IGF1R shows potent anti-tumor activity and represents a potential treatment for RAS-mutated rhabdomyosarcoma.

More Related Videos

Identification of EGFR and RAS Inhibitors using Caenorhabditis elegans08:12

Identification of EGFR and RAS Inhibitors using Caenorhabditis elegans

Published on: October 5, 2020

3.4K
Enhancing the Engraftment of Human Induced Pluripotent Stem Cell-derived Cardiomyocytes via a Transient Inhibition of Rho Kinase Activity08:00

Enhancing the Engraftment of Human Induced Pluripotent Stem Cell-derived Cardiomyocytes via a Transient Inhibition of Rho Kinase Activity

Published on: July 10, 2019

6.6K

Related Concept Videos

The Ras Gene02:38

The Ras Gene

The Ras-gene-encoded proteins are regulators of signaling pathways controlling cell proliferation, differentiation, or cell survival. The Ras-gene family in humans constitutes three primary members—the HRas, NRas, and KRas. These genes code for four functionally distinct yet closely related proteins—the HRas, NRas, KRas4A, and KRas4B. The involvement of mutant Ras genes in human cancer was first discovered in 1982 and is among the most common causes of human tumorigenesis.
Ras is a...
7.3K
Nucleosome Remodeling02:54

Nucleosome Remodeling

Nucleosomes are the basic units of chromatin compaction. Each nucleosome consists of the DNA bound tightly around a histone core, which makes the DNA inaccessible to DNA binding proteins such as DNA polymerase and RNA polymerase. Hence, the fundamental problem is to ensure access to DNA when appropriate, despite the compact and protective chromatin structure.
Nucleosome remodeling complex
Eukaryotic cells have specialized enzymes called ATP-dependent nucleosome remodeling enzymes. These enzymes...
11.2K
Small GTPases - Ras and Rho01:24

Small GTPases - Ras and Rho

Ras and Rho are small monomeric GTPases that act downstream of receptor tyrosine kinase (RTK) and regulate various cellular processes. These GTPases switch between active and inactive states by binding to guanine nucleotides.
Three regulatory proteins control their activity:
5.5K
Feedback Inhibition00:46

Feedback Inhibition

Biochemical reactions are occurring constantly in cells, converting starting substances to different products, usually with the help of enzymes that speed the reactions. Without enzymes, it would take far too long for most reactions to occur to be useful to the cell!
57.2K
Bone Remodeling01:40

Bone Remodeling

Bone remodeling is a continuous and balanced process of bone resorption by osteoclasts and bone formation by osteoblasts. In adults, it helps maintain bone mass and calcium homeostasis. While mechanical stress can stimulate turnover as part of the normal maintenance and reparative process, several hormones also regulate bone remodeling.
40.5K
Osteoclasts in Bone Remodeling01:31

Osteoclasts in Bone Remodeling

Osteoclasts are cells responsible for bone resorption and remodeling. They originate from hematopoietic progenitor cells present in the bone marrow. Numerous progenitor cells fuse to form multinucleated cells, each with 10-20 nuclei. A single osteoclast has a diameter of 150 to 200 µM. These cells have ruffled borders that break down the underlying bone tissue and release minerals such as calcium into the blood in bone resorption. Osteoclasts cling to bones with their ruffled edges during...
4.2K