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Updated: Dec 18, 2025
Author Spotlight: Advancements in Molecular Biomarker Testing for Non-Squamous Non-Small Cell Lung Cancer
Published on: September 8, 2023
Molecular Landscape of BRAF-Mutant NSCLC Reveals an Association Between Clonality and Driver Mutations and Identifies
Marcelo V Negrao1, Victoria M Raymond2, Richard B Lanman2
1Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Introduction:
Approximately 4% of NSCLC harbor BRAF mutations, and approximately 50% of these are non-V600 mutations. Treatment of tumors harboring non-V600 mutations is challenging because of functional heterogeneity and lack of knowledge regarding their clinical significance and response to targeted agents.
Methods:
We conducted an integrative analysis of BRAF non-V600 mutations using genomic profiles of BRAF-mutant NSCLC from the Guardant360 database. BRAF mutations were categorized by clonality and class (1 and 2: RAS-independent; 3: RAS-dependent). Cell viability assays were performed in Ba/F3 models. Drug screens were performed in NSCLC cell lines.
Results:
A total of 305 unique BRAF mutations were identified. Missense mutations were most common (276, 90%), and 45% were variants of unknown significance. F468S and N581Y were identified as novel activating mutations. Class 1 to 3 mutations had higher clonality than mutations of unknown class (p < 0.01). Three patients were treated with MEK with or without BRAF inhibitors. Patients harboring G469V and D594G mutations did not respond, whereas a patient with the L597R mutation had a durable response. Trametinib with or without dabrafenib, LXH254, and lifirafenib had more potent inhibition of BRAF non-V600-mutant NSCLC cell lines than other MEK, BRAF, and ERK inhibitors, comparable with the inhibition of BRAF V600E cell line.
Conclusions:
In BRAF-mutant NSCLC, clonality is higher in known functional mutations and may allow identification of variants of unknown significance that are more likely to be oncogenic drivers. Our data indicate that certain non-V600 mutations are responsive to MEK and BRAF inhibitors. This integration of genomic profiling and drug sensitivity may guide the treatment for BRAF-mutant NSCLC.
Insights
Targeting BRAF non-V600 mutations in non-small cell lung cancer (NSCLC) is challenging. Certain non-V600 mutations show responsiveness to MEK and BRAF inhibitors, guiding future treatment strategies.
Area of Science:
- Oncology
- Genetics
- Pharmacology
Background:
- Non-small cell lung cancer (NSCLC) harbors BRAF mutations in approximately 4% of cases, with half being non-V600 types.
- BRAF non-V600 mutations present treatment challenges due to functional heterogeneity and unknown clinical significance.
Purpose of the Study:
- To conduct an integrative analysis of BRAF non-V600 mutations in NSCLC.
- To understand the clinical significance and targeted agent response of these mutations.
Main Methods:
- Genomic profiling of BRAF-mutant NSCLC from the Guardant360 database.
- Categorization of BRAF mutations by clonality and class (1, 2, 3).
- Cell viability assays and drug screens in NSCLC cell lines.
Main Results:
- Identified 305 unique BRAF mutations, with F468S and N581Y as novel activating mutations.
- Class 1-3 mutations showed higher clonality than unknown class mutations.
- Partial response observed with MEK/BRAF inhibitors for L597R mutation; no response for G469V and D594G.
Conclusions:
- Mutation clonality can help identify potentially oncogenic BRAF variants.
- Specific BRAF non-V600 mutations are sensitive to MEK and BRAF inhibitors.
- Integrated genomic profiling and drug sensitivity data can guide BRAF-mutant NSCLC treatment.
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