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Ref Type Journal Article
PMID (22113612)
Authors Poulikakos PI, Persaud Y, Janakiraman M, Kong X, Ng C, Moriceau G, Shi H, Atefi M, Titz B, Gabay MT, Salton M, Dahlman KB, Tadi M, Wargo JA, Flaherty KT, Kelley MC, Misteli T, Chapman PB, Sosman JA, Graeber TG, Ribas A, Lo RS, Rosen N, Solit DB
Title RAF inhibitor resistance is mediated by dimerization of aberrantly spliced BRAF(V600E).
Journal Vol Issue Date Pages Journal Short Title
Nature 480 7377 2011 Nov 23 387-90 Nature
URL
Abstract Text Activated RAS promotes dimerization of members of the RAF kinase family. ATP-competitive RAF inhibitors activate ERK signalling by transactivating RAF dimers. In melanomas with mutant BRAF(V600E), levels of RAS activation are low and these drugs bind to BRAF(V600E) monomers and inhibit their activity. This tumour-specific inhibition of ERK signalling results in a broad therapeutic index and RAF inhibitors have remarkable clinical activity in patients with melanomas that harbour mutant BRAF(V600E). However, resistance invariably develops. Here, we identify a new resistance mechanism. We find that a subset of cells resistant to vemurafenib (PLX4032, RG7204) express a 61-kDa variant form of BRAF(V600E), p61BRAF(V600E), which lacks exons 4-8, a region that encompasses the RAS-binding domain. p61BRAF(V600E) shows enhanced dimerization in cells with low levels of RAS activation, as compared to full-length BRAF(V600E). In cells in which p61BRAF(V600E) is expressed endogenously or ectopically, ERK signalling is resistant to the RAF inhibitor. Moreover, a mutation that abolishes the dimerization of p61BRAF(V600E) restores its sensitivity to vemurafenib. Finally, we identified BRAF(V600E) splicing variants lacking the RAS-binding domain in the tumours of six of nineteen patients with acquired resistance to vemurafenib. These data support the model that inhibition of ERK signalling by RAF inhibitors is dependent on levels of RAS-GTP too low to support RAF dimerization and identify a novel mechanism of acquired resistance in patients: expression of splicing isoforms of BRAF(V600E) that dimerize in a RAS-independent manner.

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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 A81_D380del deletion gain of function - predicted BRAF A81_D380del results in the deletion of 300 amino acids of the Braf protein from amino acids 81 to 380 (UniProt.org). A81_D380del (reported as internal deletion of exons 3-8) has not been characterized, however, due to the deletion of the CR1 autoinhibitory domain and preservation of the protein kinase domain (PMID: 23890088, PMID: 22113612, PMID: 29171936), is predicted to lead to a gain of Braf protein function.
BRAF A81_M438del deletion gain of function - predicted BRAF A81_M438del results in the deletion of 358 amino acids of the Braf protein from amino acids 81 to 438 (UniProt.org). A81_M438del (reported as internal deletion of exons 3-10) has not been characterized, however, due to the deletion of the CR1 autoinhibitory domain and preservation of the protein kinase domain (PMID: 23890088, PMID: 22113612, PMID: 29171936), is predicted to lead to a gain of Braf protein function.
BRAF del exon2-10 deletion gain of function - predicted BRAF del exon2-10 indicates the deletion of exons 2-10 of the BRAF gene (PMID: 22113612). Del exon2-10 has been associated with resistance to 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 exon2-8 deletion gain of function - predicted BRAF del exon2-8 indicates the deletion of exons 2-8 of the BRAF gene (PMID: 38691346). Del exon2-8 has been associated with resistance to Mek inhibitors (PMID: 35724767) 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
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
BRAF G203_G393del deletion gain of function - predicted BRAF G203_G393del results in the deletion of 91 amino acids of the Braf protein from amino acids 203 to 393 (UniProt.org). G203_G393del (reported as internal deletion of exons 5-9) has not been characterized, however, due to the disruption of the CR1 autoinhibitory domain and preservation of the protein kinase domain (PMID: 23890088, PMID: 22113612, PMID: 29171936), is predicted to lead to a gain of Braf protein function.
BRAF V169_D380del deletion gain of function - predicted BRAF V169_D380del results in the deletion of 212 amino acids of the Braf protein from amino acids 169 to 380 (UniProt.org). V169_D380del (reported as internal deletion of exons 4-8) has not been characterized, however, due to the deletion of the CR1 autoinhibitory domain and preservation of the protein kinase domain (PMID: 23890088, PMID: 22113612, PMID: 29171936), is predicted to lead to a gain of Braf protein function.
BRAF V169_G327del deletion gain of function - predicted BRAF V169_G327del results in the deletion of 159 amino acids of the Braf protein from amino acids 169 to 327 (UniProt.org). V169_G327del (reported as internal deletion of exons 4-7) has not been characterized, however, due to the deletion of the CR1 autoinhibitory domain and preservation of the protein kinase domain (PMID: 23890088, PMID: 22113612, PMID: 29171936), is predicted to lead to a gain of Braf protein function.
BRAF V47_D380del deletion gain of function - predicted BRAF V47_D380del results in the deletion of 334 amino acids of the Braf protein from amino acids 47 to 380 (UniProt.org). V47_D380del (reported as internal deletion of exons 2-8) has been associated with resistance to Mek inhibitors in a patient (PMID: 29171936), 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 V47_G327del deletion gain of function - predicted BRAF V47_G327del results in the deletion of 281 amino acids of the Braf protein from amino acids 47 to 327 (UniProt.org). V47_G327del (reported as internal deletion of exons 2-7) has not been characterized, however, due to the deletion of the CR1 autoinhibitory domain and preservation of the protein kinase domain (PMID: 23890088, PMID: 22113612, PMID: 29171936), is predicted to lead to a gain of Braf protein function.
BRAF V47_G393del deletion gain of function - predicted BRAF V47_G393del results in the deletion of 347 amino acids of the Braf protein from amino acids 47 to 393 (UniProt.org). V47_G393del (reported as internal deletion of exons 2-9) has not been characterized, however, due to the deletion of the CR1 autoinhibitory domain and preservation of the protein kinase domain (PMID: 23890088, PMID: 22113612, PMID: 29171936), is predicted to lead to a gain of Braf protein function.
BRAF V47_M438del deletion gain of function - predicted BRAF V47_M438del results in the deletion of 392 amino acids of the Braf protein from amino acids 47 to 438 (UniProt.org). V47_M438del (reported as internal deletion of exons 2-10) has been associated with acquired resistance to a Braf inhibitor in a patient (PMID: 32669268), 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, PMID: 29171936). Y
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
BRAF del exon2-8 BRAF V600E melanoma predicted - resistant Vemurafenib Case Reports/Case Series Actionable In a clinical case study, a deletion of BRAF exons 2-8 was identified in the post-progression biopsy of a melanoma patient harboring BRAF V600E who was treated with Zelboraf (vemurafenib) (PMID: 22113612). 22113612
BRAF del exon4-8 BRAF V600E melanoma predicted - resistant Vemurafenib Case Reports/Case Series Actionable In a clinical case study, a deletion of BRAF exons 4-8 was identified in the post-progression biopsy of a melanoma patient harboring BRAF V600E who was treated with Zelboraf (vemurafenib) (PMID: 22113612). 22113612
BRAF del exon2-10 BRAF V600E melanoma predicted - resistant Vemurafenib Case Reports/Case Series Actionable In a clinical case study, a deletion of BRAF exons 2-10 was identified in the post-progression biopsy of three melanoma patients harboring BRAF V600E who were treated with Zelboraf (vemurafenib) (PMID: 22113612). 22113612
BRAF del exon4-10 BRAF V600E melanoma predicted - resistant Vemurafenib Case Reports/Case Series Actionable In a clinical case study, a deletion of BRAF exons 4-10 was identified in the post-progression biopsy of a melanoma patient harboring BRAF V600E who was treated with Zelboraf (vemurafenib) (PMID: 22113612). 22113612