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Ref Type

Journal Article

PMID

(29171936)

Authors

Johnson DB, Childress MA, Chalmers ZR, Frampton GM, Ali SM, Rubinstein SM, Fabrizio D, Ross JS, Balasubramanian S, Miller VA, Stephens PJ, Sosman JA, Lovly CM

Title

BRAF internal deletions and resistance to BRAF/MEK inhibitor therapy.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Pigment cell & melanoma research	31	3	2018 05	432-436	Pigment Cell Melanoma Res

URL

Abstract Text

BRAF and MEK inhibitors have improved clinical outcomes in advanced, BRAFV600 -mutated melanomas. Acquired resistance occurs in most patients, with numerous and diverse drivers. We obtained pretreatment and progression biopsies from a patient who progressed on dabrafenib and trametinib. In addition to a preserved BRAFV600E mutation, an internal deletion (rearrangement) of BRAF was observed in the progression sample. This deletion involved exons 2-8, which includes the Ras-binding domain, and is analogous to previously documented BRAF fusions and splice variants known to reactivate RAS-RAF-MEK-ERK signaling. In a large cohort of melanomas, 10 additional internal deletions were identified (0.4% of all melanomas; nine of which had concurrent BRAF mutations), as well as sporadically in other tumor types. Thus, we describe a novel mechanism of resistance to BRAF and MEK inhibition.

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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.

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Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
BRAF V47_D380del	melanoma	predicted - resistant	Dabrafenib + Trametinib	Case Reports/Case Series	Actionable	In a clinical case study, a melanoma patient developed progressive disease after initial response to Tafinlar (dabrafenib) and Mekinist (trametinib) combination treatment, BRAF V47_D380del was identified as an acquired mutation in the progressing lesion along with mutations presented in both primary and progressing lesions, including BRAF V600E, PTEN G129E, CDKN2A/B loss, and TERT promoter mutations (PMID: 29171936).	29171936

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