Related Experiment Video
Updated: Mar 15, 2026
Characterize Disease-related Mutants of RAF Family Kinases by Using a Set of Practical and Feasible Methods
Published on: July 17, 2019
Acquired resistance to BRAF inhibition in BRAFV600E mutant gliomas
Tsun-Wen Yao1, Jie Zhang1, Michael Prados1,2
1Department of Pediatrics, University of California San Francisco, San Francisco, CA, USA.
Abstract:
Activating mutation of BRAF is a common finding in pediatric gliomas. As many as 14% of high grade and up to 66% of certain subtypes of low grade pediatric glioma have the BRAFV600E mutation. Small molecule inhibitors that selectively target BRAFV600E are FDA approved for melanoma and have shown significant efficacy in treating BRAFV600E glioma in pre-clinical trials. Despite showing initial anti-tumor activity, acquired drug resistance significantly limits the benefit from being treated with BRAFV600E inhibitors. Here, we have identified molecular responses to BRAFV600E inhibitor treatment in human glioma models that have substantial clinical implications. Specifically, we show that BRAFV600E inhibitor resistant cells upregulate pro-survival mediators such as Wnt, and additionally increase receptor tyrosine kinase activity, including EGFR and Axl, promoting resistance to BRAFV600E inhibition. Our results suggest strategies to circumvent acquired resistance to BRAFV600E inhibitor therapy, and thereby improve outcomes for patients with BRAFV600E gliomas.
Insights
BRAF V600E inhibitors show promise for pediatric gliomas but face resistance. Resistant cells activate Wnt and receptor tyrosine kinases like EGFR, suggesting new therapeutic strategies to overcome this resistance.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Activating BRAF mutations, particularly BRAFV600E, are prevalent in pediatric gliomas.
- FDA-approved BRAFV600E inhibitors demonstrate efficacy in preclinical glioma models.
Purpose of the Study:
- To identify molecular mechanisms underlying acquired resistance to BRAFV600E inhibitors in human glioma models.
- To explore strategies for overcoming drug resistance and improving patient outcomes.
Main Methods:
- Utilized human glioma models to investigate responses to BRAFV600E inhibitor treatment.
- Analyzed molecular changes, including pro-survival mediator and receptor tyrosine kinase activity, in resistant cells.
Main Results:
- BRAFV600E inhibitor-resistant glioma cells upregulate pro-survival mediators, notably Wnt signaling.
- Increased activity of receptor tyrosine kinases, including EGFR and Axl, was observed in resistant cells, contributing to therapeutic resistance.
Conclusions:
- Acquired resistance to BRAFV600E inhibitors in gliomas involves the upregulation of Wnt and increased receptor tyrosine kinase activity.
- Targeting these resistance pathways presents a promising strategy to enhance the efficacy of BRAFV600E inhibitor therapy in pediatric gliomas.
More Related Videos
Related Concept Videos
02:56Treatment Resistant Cancers
01:20The Retinoblastoma Gene
The first-ever tumor suppressor gene called Rb was identified in retinoblastoma - a rare eye tumor in children. In inherited forms of the disease, a child inherits one defective copy of the Rb gene, which predisposes them to retinoblastoma. However,...