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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
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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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Showing 1 to 13 of 13 entries

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance
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
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	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	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	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

Showing 1 to 13 of 13 entries

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Showing 1 to 4 of 4 entries

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
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 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 exon4-10 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
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

Showing 1 to 4 of 4 entries

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