Polymorphisms at site 469 of B-RAF protein associated with skin melanoma may be correlated with dabrafenib resistance: An <i>in silico</i> study

Chatterjee, Samadrita; Chakraborty, Rajkumar; Hasija, Yasha

doi:10.1080/07391102.2021.1950571

Cited by 2 publications

(3 citation statements)

References 78 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Studies in other cancers may also provide hints on the therapeutic sensitivity of BRAF G469-mutant NSCLC. 7,18 G469V was predicted as deleterious in an in silico study of skin melanoma, and molecular dynamic simulations suggested that G469V had lower binding energy than the WT variant for dabrafenib. 18 While more clinical validation is needed, these results suggested potential resistance to currently available BRAF inhibitors and EGFR blockade, thereby highlighting the significance of EGFR TKIs in targeting G469-mutated BRAF.…”

Section: Discussionmentioning

confidence: 99%

“…7,18 G469V was predicted as deleterious in an in silico study of skin melanoma, and molecular dynamic simulations suggested that G469V had lower binding energy than the WT variant for dabrafenib. 18 While more clinical validation is needed, these results suggested potential resistance to currently available BRAF inhibitors and EGFR blockade, thereby highlighting the significance of EGFR TKIs in targeting G469-mutated BRAF. In this study, we revealed a combined prevalence of 0.39% in NSCLC, corresponding approximately to 6000 deaths per year based on the 2020 GLOBOCAN statistics.…”

Section: Discussionmentioning

confidence: 99%

“…Studies in other cancers may also provide hints on the therapeutic sensitivity of BRAF G469‐mutant NSCLC 7,18 . G469V was predicted as deleterious in an in silico study of skin melanoma, and molecular dynamic simulations suggested that G469V had lower binding energy than the WT variant for da braf enib 18 .…”

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

A large‐scale, multicenter characterization of BRAF G469V/A‐mutant non‐small cell lung cancer

Wu,

Feng,

et al. 2024

Cancer Medicine

View full text Add to dashboard Cite

BackgroundMutated 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.MethodsWe 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.ResultsBRAF 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.ConclusionOur 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.

show abstract

Section: Discussionmentioning

confidence: 99%