Reference Detail

Ref Type

Journal Article

PMID

(33216826)

Authors

Clark ME, Rizos H, Pereira MR, McEvoy AC, Marsavela G, Calapre L, Meehan K, Ruhen O, Khattak MA, Meniawy TM, Long GV, Carlino MS, Menzies AM, Millward M, Ziman M, Gray ES

Title

Detection of BRAF splicing variants in plasma-derived cell-free nucleic acids and extracellular vesicles of melanoma patients failing targeted therapy therapies.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Oncotarget	11	44	2020 Nov 03	4016-4027	Oncotarget

URL

Abstract Text

The analysis of plasma circulating tumour nucleic acids provides a non-invasive approach to assess disease burden and the genetic evolution of tumours in response to therapy. BRAF splicing variants are known to confer melanoma resistance to BRAF inhibitors. We developed a test to screen cell-free RNA (cfRNA) for the presence of BRAF splicing variants. Custom droplet digital PCR assays were designed for the detection of BRAF splicing variants p61, p55, p48 and p41 and then validated using RNA from cell lines carrying these variants. Evaluation of plasma from patients with reported objective response to BRAF/MEK inhibition followed by disease progression was revealed by increased circulating tumour DNA (ctDNA) in 24 of 38 cases at the time of relapse. Circulating BRAF splicing variants were detected in cfRNA from 3 of these 38 patients; two patients carried the BRAF p61 variant and one the p55 variant. In all three cases the presence of the splicing variant was apparent only at the time of progressive disease. BRAF p61 was also detectable in plasma of one of four patients with confirmed BRAF splicing variants in their progressing tumours. Isolation and analysis of RNA from extracellular vesicles (EV) from resistant cell lines and patient plasma demonstrated that BRAF splicing variants are associated with EVs. These findings indicate that in addition to plasma ctDNA, RNA carried by EVs can provide important tumour specific information.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance
BRAF	del exon4-10	deletion	gain of function - predicted	BRAF del exon4-10 indicates the deletion of exons 4-10 of the BRAF gene (PMID: 33216826). Del exon4-10 has been associated with resistance to MEK inhibitors (PMID: 33216826) and RAF inhibitors (PMID: 22113612) in patients, and is predicted to lead to a gain of Braf protein function due to the deletion of the CR1 autoinhibitory domain and preservation of the protein kinase domain (PMID: 23890088, PMID: 22113612).	Y
BRAF	del exon4-8	deletion	gain of function - predicted	BRAF del exon4-8 indicates the deletion of exons 4-8 of the BRAF gene (PMID: 33216826). Del exon4-8 has been associated with resistance to MEK inhibitors (PMID: 33216826) and RAF inhibitors (PMID: 22113612) in culture, and is predicted to lead to a gain of Braf protein function due to the deletion of the CR1 autoinhibitory domain and preservation of the protein kinase domain (PMID: 23890088, PMID: 22113612).	Y

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
BRAF del exon4-8 BRAF V600E	melanoma	predicted - resistant	Dabrafenib + Trametinib	Case Reports/Case Series	Actionable	In a clinical case study, a BRAF exon 4-8 deletion variant (reported as p61) was identified in the post-progression plasma ctDNA of two patients with metastatic melanoma harboring BRAF V600E who previously responded to treatment with the combination of Tafinlar (dabrafenib) and Mekinist (trametinib) (PMID: 33216826).	33216826
BRAF del exon4-10 BRAF V600K	melanoma	predicted - resistant	Dabrafenib + Trametinib	Case Reports/Case Series	Actionable	In a clinical case study, a BRAF exon 4-10 deletion (reported as p55) variant was identified in the post-progression plasma ctRNA of a patient with metastatic melanoma harboring BRAF V600K who previously responded to treatment with the combination of Tafinlar (dabrafenib) and Mekinist (trametinib) (PMID: 33216826).	33216826