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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. | ||||||||||||
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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. |
Molecular Profile | Treatment Approach |
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Gene Name | Source | Synonyms | Protein Domains | Gene Description | Gene Role |
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Therapy Name | Drugs | Efficacy Evidence | Clinical Trials |
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Drug Name | Trade Name | Synonyms | Drug Classes | Drug Description |
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Gene | Variant | Impact | Protein Effect | Variant Description | Associated with drug Resistance |
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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 |
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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 |