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Updated: May 30, 2026
Characterize Disease-related Mutants of RAF Family Kinases by Using a Set of Practical and Feasible Methods
Published on: July 17, 2019
Targeting oncogenic BRAF in human cancer
Christine A Pratilas1, Feng Xing, David B Solit
1Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
Abstract:
Mitogen Activated Protein Kinase (MAPK) pathway activation is a frequent event in human cancer and is often the result of activating mutations in the BRAF and RAS oncogenes. BRAF missense mutations, the vast majority of which are V600E, occur in approximately 8% of human tumors. These kinase domain mutations, which are non-overlapping in distribution with RAS mutations, are observed most frequently in melanoma but are also common in tumors arising in the colon, thyroid, lung, and other sites. Supporting its classification as an oncogene, (V600E)BRAF stimulates ERK signaling, induces proliferation, and is capable of promoting transformation. Given the frequent occurrence of BRAF mutations in human cancer and the continued requirement for BRAF activity in the tumors in which it is mutated, efforts are underway to develop targeted inhibitors of BRAF and its downstream effectors. These agents offer the possibility of greater efficacy and less toxicity than the systemic therapies currently available for tumors driven by activating mutations of MAPK pathway components. Early clinical results with the BRAF-selective inhibitors PLX4032 and GSK2118436 suggest that this strategy will prove successful in a select group of patients whose tumors are driven by oncogenic BRAF.
Insights
Activating BRAF mutations drive cancer by promoting cell proliferation. Targeted inhibitors show promise for treating cancers with these specific BRAF mutations, offering improved efficacy and reduced toxicity.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Genetics
Background:
- Mitogen Activated Protein Kinase (MAPK) pathway activation is common in human cancers.
- Activating mutations in BRAF and RAS oncogenes frequently drive MAPK pathway activation.
- BRAF V600E mutations occur in approximately 8% of human tumors, particularly melanoma, colon, thyroid, and lung cancers.
Purpose of the Study:
- To investigate the role of BRAF mutations in cancer development.
- To explore the potential of targeted BRAF inhibitors for cancer therapy.
- To evaluate the efficacy and toxicity of BRAF-selective inhibitors.
Main Methods:
- Analysis of BRAF and RAS oncogene mutations in human tumors.
- Assessment of (V600E)BRAF's oncogenic properties, including ERK signaling stimulation, proliferation, and transformation.
- Clinical evaluation of BRAF-selective inhibitors (PLX4032, GSK2118436).
Main Results:
- BRAF mutations, predominantly V600E, are oncogenic drivers in various human cancers.
- (V600E)BRAF promotes cell proliferation and transformation.
- Early clinical trials with BRAF inhibitors demonstrate promising results for specific patient groups.
Conclusions:
- Targeted inhibition of BRAF offers a promising therapeutic strategy for BRAF-mutated cancers.
- BRAF inhibitors may provide greater efficacy and reduced toxicity compared to current systemic therapies.
- The development of BRAF-selective agents holds potential for successful treatment of tumors driven by oncogenic BRAF.
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