Related Experiment Video
Updated: Jan 6, 2026
Characterize Disease-related Mutants of RAF Family Kinases by Using a Set of Practical and Feasible Methods
Published on: July 17, 2019
Epigenetic Mechanisms of Escape from BRAF Oncogene Dependency
Mehwish Khaliq1,2, Mohammad Fallahi-Sichani3,4,5
1Department of Biomedical Engineering, University of Michigan Medical School, Ann Arbor, MI 48109, USA. mehwishk@umich.edu.
Abstract:
About eight percent of all human tumors (including 50% of melanomas) carry gain-of-function mutations in the BRAF oncogene. Mutated BRAF and subsequent hyperactivation of the MAPK signaling pathway has motivated the use of MAPK-targeted therapies for these tumors. Despite great promise, however, MAPK-targeted therapies in BRAF-mutant tumors are limited by the emergence of drug resistance. Mechanisms of resistance include genetic, non-genetic and epigenetic alterations. Epigenetic plasticity, often modulated by histone-modifying enzymes and gene regulation, can influence a tumor cell's BRAF dependency and therefore, response to therapy. In this review, focusing primarily on class 1 BRAF-mutant cells, we will highlight recent work on the contribution of epigenetic mechanisms to inter- and intratumor cell heterogeneity in MAPK-targeted therapy response.
Insights
BRAF-mutant tumors often develop resistance to MAPK-targeted therapies. Epigenetic mechanisms contribute to this resistance by influencing tumor cell heterogeneity and therapy response.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Genetics
Background:
- Gain-of-function mutations in the BRAF oncogene are present in approximately 8% of human tumors, notably 50% of melanomas.
- Hyperactivation of the MAPK signaling pathway due to BRAF mutations drives tumor growth and is a target for therapy.
- Drug resistance remains a significant challenge in treating BRAF-mutant tumors with MAPK-targeted therapies.
Purpose of the Study:
- To review the contribution of epigenetic mechanisms to drug resistance in BRAF-mutant tumors.
- To highlight how epigenetic plasticity influences tumor cell heterogeneity and therapy response.
- To focus on class 1 BRAF-mutant cells and their response to MAPK-targeted therapy.
Main Methods:
- Literature review focusing on epigenetic mechanisms in BRAF-mutant cancers.
- Analysis of research on histone-modifying enzymes and gene regulation in therapy resistance.
- Examination of inter- and intratumor cell heterogeneity in response to MAPK-targeted therapy.
Main Results:
- Epigenetic alterations are key mechanisms driving resistance to MAPK-targeted therapies.
- Epigenetic plasticity can modulate a tumor cell's dependency on BRAF signaling.
- Heterogeneity within and between tumors contributes to variable responses to therapy.
Conclusions:
- Epigenetic mechanisms play a crucial role in the development of resistance to MAPK-targeted therapies in BRAF-mutant cancers.
- Understanding epigenetic contributions to tumor heterogeneity is vital for improving therapeutic strategies.
- Targeting epigenetic pathways may offer novel approaches to overcome drug resistance.
Related Concept Videos
02:38The Ras Gene
Ras is a...
01:07MAPK Signaling Cascades
03:03mTOR Signaling and Cancer Progression
The mTOR pathway or the...
02:53Adaptive Mechanisms in Cancer Cells
Some of the advantages that cancer cells have on normal cells include - enhanced ability to divide without terminally differentiating, induce new blood vessel formation,...
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,...
01:37Epigenetic Regulation
X-chromosome...