Related Experiment Video
Updated: Apr 11, 2026
Tumor Treating Field Therapy in Combination with Bevacizumab for the Treatment of Recurrent Glioblastoma
Published on: October 27, 2014
EGFR blockade prevents glioma escape from BRAFV600E targeted therapy
Tsun-Wen Yao1, Jie Zhang1, Michael Prados1,2
1Departments of Pediatrics, University of California San Francisco, San Francisco, CA, USA.
Abstract:
Mutational activation of BRAF(BRAF(V600E)) occurs in pediatric glioma and drives aberrant MAPK signaling independently of upstream cues. Targeted monotherapy against BRAF(V600E) displays efficacy in pre-clinical models of glioma, however xenograft tumors adapt rapidly and escape from the growth-inhibitory effects of BRAF-targeted therapy. Here, we show that intrinsic resistance to a BRAF(V600E) specific inhibitor stems, in part, from feedback activation of EGFR and downstream signaling pathways. BRAF(V600E) inhibition suppresses MAPK signaling, which in turn downregulates the EGFR phosphatase PTPN9, resulting in sustained EGFR phosphorylation and enhanced EGFR activity. We demonstrated that overexpression of PTPN9 reduces EGFR phosphorylation and cooperates with BRAF(V600E) inhibitor PLX4720 to reduce MAPK and Akt signaling, resulting in decreased glioma cell viability. Moreover, pharmacologic inhibition of EGFR combined with inhibition of BRAF(V600E) to reduce growth of glioma cell lines and orthotopic glioma xenograft by decreasing tumor cell proliferation while increasing apoptosis, with resultant significant extension of animal subject survival. Our data support clinical evaluation of BRAF(V600E) and EGFR targeted therapy in treating BRAF(V600E) glioma.
Insights
Targeting BRAF(V600E) in pediatric glioma shows promise, but resistance emerges due to EGFR activation. Combining BRAF and EGFR inhibitors effectively reduces tumor growth and improves survival.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Signaling
Background:
- BRAF(V600E) mutations drive pediatric glioma by activating MAPK signaling.
- BRAF-targeted monotherapy shows initial efficacy but is often overcome by tumor resistance mechanisms.
Purpose of the Study:
- To investigate the mechanisms of intrinsic resistance to BRAF(V600E) inhibitors in glioma.
- To evaluate the efficacy of combined BRAF(V600E) and EGFR inhibition in preclinical glioma models.
Main Methods:
- Investigated feedback activation of EGFR and downstream pathways upon BRAF(V600E) inhibition.
- Utilized BRAF(V600E) inhibitor PLX4720 and EGFR pharmacologic inhibition.
- Assessed effects on MAPK, Akt signaling, cell viability, proliferation, and apoptosis in glioma cell lines and xenografts.
Main Results:
- BRAF(V600E) inhibition leads to feedback activation of EGFR via downregulation of PTPN9.
- Overexpression of PTPN9 abrogates EGFR phosphorylation and enhances BRAF inhibitor efficacy.
- Combined BRAF(V600E) and EGFR inhibition significantly reduces tumor growth, increases apoptosis, and extends survival in preclinical models.
Conclusions:
- Intrinsic resistance to BRAF(V600E) inhibitors in glioma is partly mediated by EGFR feedback activation.
- Combination therapy targeting both BRAF(V600E) and EGFR represents a promising strategy for pediatric glioma.
- Clinical evaluation of combined BRAF(V600E) and EGFR targeted therapy is warranted for BRAF(V600E) glioma.
More Related Videos
Related Concept Videos
02:38Mitogens and the Cell Cycle
02:57Targeted Cancer Therapies
There are several types of targeted therapies against...
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,...
01:27Tumor Immunotherapy