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Characterize Disease-related Mutants of RAF Family Kinases by Using a Set of Practical and Feasible Methods
Published on: July 17, 2019
A large-scale, multicenter characterization of BRAF G469V/A-mutant non-small cell lung cancer
1Department of Surgical Oncology, Shanghai Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Background:
Mutated BRAF is identified in 1%-5% non-small cell lung cancer (NSCLC) patients, with non-V600 mutations accounting for 50%-70% of these. The most common non-V600 mutation is BRAF G469V/A. Currently, there are no targeted therapies available for non-V600 mutated patients. A recent report provided interesting preclinical evidence revealing sensitivity of BRAF G469V to epidermal growth factor receptor (EGFR) inhibitors, raising the possibility of repurposing anti-EGFR agents. It is therefore worthy to characterize the clinical and molecular features of BRAF G469V/A-mutant NSCLC to provide more insights for precision therapy.
Methods:
We conducted a retrospective screening of 25,694 Chinese patients with advanced or metastatic NSCLC to identify individuals with mutated BRAF. Additionally, we performed similar screenings on patients with adenocarcinoma (LUAD) from The Cancer Genome Atlas (TCGA) cohort (n = 567) and the MSKCC cohort (n = 1152). Subsequently, we characterized the clinical and molecular features of the patients carrying BRAF mutations.
Results:
BRAF G469V was identified in 28 (0.1%) patients from the Chinese NSCLC cohort and 5 (0.9%) from TCGA-LUAD. Notably, none was identified in the MSKCC cohort. G469A was found in 79 (0.3%) Chinese patients, 2 (0.4%) from TCGA-LUAD, and 9 (0.8%) from the MSKCC cohort. Relative allele frequency analysis suggested most BRAF mutations as driven clones. Tumor mutation burden (median 4 mutations/Mb) was not significantly different between patients carrying G469V, G469A, V600E, or other BRAF mutations. Surprisingly, KRAS mutations were found in approximately 50% of patients with G469V mutation and about 8% of patients with G469A mutation, representing a prominent potential resistance mechanism against EGFR inhibitors. Structural modeling suggested BRAF G469V and G469A as binding partners of gefitinib.
Conclusion:
Our large-scale analysis characterized the prevalence and mutational landscape of BRAF G469V/A-mutant NSCLC and proposed gefitinib as a potential option, providing a basis for further investigations on treating BRAF-mutated NSCLC.
Insights
Non-V600 BRAF mutations, common in non-small cell lung cancer (NSCLC), show potential sensitivity to EGFR inhibitors. This study identifies BRAF G469V/A mutations and suggests gefitinib as a treatment option for NSCLC patients.
Area of Science:
- Oncology
- Genetics
- Pharmacology
Background:
- BRAF mutations occur in 1%-5% of non-small cell lung cancer (NSCLC) patients, with non-V600 mutations representing 50%-70% of these.
- BRAF G469V/A are the most frequent non-V600 mutations, lacking targeted therapies.
- Preclinical data suggest BRAF G469V sensitivity to epidermal growth factor receptor (EGFR) inhibitors, indicating potential repurposing of anti-EGFR agents.
Purpose of the Study:
- To characterize the clinical and molecular features of BRAF G469V/A-mutant NSCLC.
- To provide insights for precision therapy in BRAF-mutated NSCLC.
- To evaluate gefitinib as a potential therapeutic option for BRAF G469V/A-mutant NSCLC.
Main Methods:
- Retrospective screening of 25,694 Chinese NSCLC patients for BRAF mutations.
- Screening of TCGA (n=567) and MSKCC (n=1152) LUAD cohorts for BRAF mutations.
- Clinical and molecular characterization of patients with BRAF mutations.
Main Results:
- BRAF G469V identified in 0.1% of Chinese NSCLC and 0.9% of TCGA-LUAD.
- BRAF G469A identified in 0.3% of Chinese NSCLC, 0.4% of TCGA-LUAD, and 0.8% of MSKCC.
- KRAS mutations observed in ~50% of G469V and ~8% of G469A cases, suggesting potential EGFR inhibitor resistance; structural modeling indicates BRAF G469V/A bind gefitinib.
Conclusions:
- This large-scale analysis defines the prevalence and mutational landscape of BRAF G469V/A-mutant NSCLC.
- Gefitinib is proposed as a potential therapeutic option for BRAF G469V/A-mutant NSCLC.
- Findings provide a basis for further investigation into treating BRAF-mutated NSCLC.
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