Related Experiment Video
Updated: Feb 13, 2026
RNAi Screening to Identify Postembryonic Phenotypes in C. elegans
Published on: February 13, 2012
Functional screening of FGFR4-driven tumorigenesis identifies PI3K/mTOR inhibition as a therapeutic strategy in
Timothy McKinnon1, Rosemarie Venier1, Marielle Yohe2
1Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada.
Abstract:
Rhabdomyosarcoma (RMS) is the most common pediatric soft tissue sarcoma and outcomes have stagnated, highlighting a need for novel therapies. Genomic analysis of RMS has revealed that alterations in the receptor tyrosine kinase (RTK)/RAS/PI3K axis are common and that FGFR4 is frequently mutated or overexpressed. Although FGFR4 is a potentially druggable receptor tyrosine kinase, its functions in RMS are undefined. This study tested FGFR4-activating mutations and overexpression for the ability to generate RMS in mice. Murine tumor models were subsequently used to discover potential therapeutic targets and to test a dual PI3K/mTOR inhibitor in a preclinical setting. Specifically, we provide the first mechanistic evidence of differential potency in the most common human RMS mutations, V550E or N535K, compared to FGFR4wt overexpression as murine myoblasts expressing FGFR4V550E undergo higher rates of cellular transformation, engraftment into mice, and rapidly form sarcomas that highly resemble human RMS. Murine tumor cells overexpressing FGFR4V550E were tested in an in vitro dose-response drug screen along with human RMS cell lines. Compounds were grouped by target class, and potency was determined using average percentage of area under the dose-response curve (AUC). RMS cells were highly sensitive to PI3K/mTOR inhibitors, in particular, GSK2126458 (omipalisib) was a potent inhibitor of FGFR4V550E tumor-derived cell and human RMS cell viability. FGFR4V550E-overexpressing myoblasts and tumor cells had low nanomolar GSK2126458 EC50 values. Mass cytometry using mouse and human RMS cell lines validated GSK2126458 specificity at single-cell resolution, decreasing the abundance of phosphorylated Akt as well as decreasing phosphorylation of the downstream mTOR effectors 4ebp1, Eif4e, and S6. Moreover, PI3K/mTOR inhibition also robustly decreased the growth of RMS tumors in vivo. Thus, by developing a preclinical platform for testing novel therapies, we identified PI3K/mTOR inhibition as a promising new therapy for this devastating pediatric cancer.
Insights
Rhabdomyosarcoma (RMS) research shows FGFR4 mutations drive cancer. A dual PI3K/mTOR inhibitor, GSK2126458, effectively reduced tumor growth in preclinical models, offering a promising new therapy for pediatric RMS.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Rhabdomyosarcoma (RMS) is a common pediatric soft tissue sarcoma with stagnant outcomes, necessitating novel therapeutic strategies.
- Genomic analyses reveal frequent alterations in the receptor tyrosine kinase (RTK)/RAS/PI3K pathway, including mutations and overexpression of FGFR4, a druggable target.
- The precise functions of FGFR4 in RMS pathogenesis remain largely undefined.
Purpose of the Study:
- To investigate the oncogenic potential of FGFR4-activating mutations and overexpression in RMS development.
- To establish and utilize murine tumor models for identifying therapeutic targets.
- To evaluate the efficacy of a dual PI3K/mTOR inhibitor as a potential treatment for RMS in a preclinical setting.
Main Methods:
- Development of murine models expressing specific FGFR4 mutations (V550E, N535K) or wild-type (wt) overexpression to assess RMS generation.
- In vitro drug screening of RMS cell lines (murine and human) using a panel of compounds, assessing potency via area under the dose-response curve (AUC).
- Mass cytometry analysis to validate drug specificity and downstream signaling inhibition (phosphorylated Akt, mTOR effectors) in RMS cells.
Main Results:
- Murine myoblasts expressing FGFR4V550E exhibited enhanced cellular transformation, engraftment, and rapid formation of RMS tumors resembling human disease, establishing a relevant preclinical model.
- RMS cells demonstrated high sensitivity to PI3K/mTOR inhibitors, with GSK2126458 (omipalisib) showing potent inhibition of cell viability in both FGFR4V550E-derived and human RMS cell lines (low nanomolar EC50 values).
- In vivo studies confirmed that PI3K/mTOR inhibition significantly suppressed RMS tumor growth.
Conclusions:
- FGFR4-activating mutations, particularly V550E, play a significant role in RMS tumorigenesis, providing a mechanistic link between genetic alterations and disease.
- Dual PI3K/mTOR inhibition, exemplified by GSK2126458, represents a promising therapeutic strategy for pediatric RMS.
- The developed preclinical platform enables effective testing of novel therapies for RMS, paving the way for clinical translation.
More Related Videos
07:15Mechanism of Kemeng Fang's Inhibition of Podocyte Apoptosis in Rats with Membranous Nephropathy through the PI3K/AKT Signaling Pathway
Published on: August 23, 2024
05:51A Strategy to Identify de Novo Mutations in Common Disorders such as Autism and Schizophrenia
Published on: June 15, 2011
Related Concept Videos
01:22PI3K/mTOR/AKT Signaling Pathway
03:03mTOR Signaling and Cancer Progression
The mTOR pathway or the...
00:46Feedback Inhibition
01:30Enzyme Inhibition
01:13Therapeutic Index
01:27ATP Driven Pumps I: An Overview
There are four main types of ATP-driven pumps - P-type, V-type, F-type, and ABC transporter. All these pumps are of varying complexities and...