Reference Detail

Ref Type

Journal Article

PMID

(29880583)

Authors

Wang J, Yao Z, Jonsson P, Allen AN, Qin ACR, Uddin S, Dunkel IJ, Petriccione M, Manova K, Haque S, Rosenblum MK, Pisapia DJ, Rosen N, Taylor BS, Pratilas CA

Title

A Secondary Mutation in BRAF Confers Resistance to RAF Inhibition in a BRAFV600E-Mutant Brain Tumor.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Cancer discovery	8	9	2018 Sep	1130-1141	Cancer Discov

URL

Abstract Text

BRAFV600E hyperactivates ERK and signals as a RAF inhibitor-sensitive monomer. Although RAF inhibitors can produce impressive clinical responses in patients with mutant BRAF tumors, the mechanisms of resistance to these drugs are incompletely characterized. Here, we report a complete response followed by clinical progression in a patient with a BRAFV600E-mutant brain tumor treated with dabrafenib. Whole-exome sequencing revealed a secondary BRAFL514V mutation at progression that was not present in the pretreatment tumor. Expressing BRAFV600E/L514V induces ERK signaling, promotes RAF dimer formation, and is sufficient to confer resistance to dabrafenib. Newer RAF dimer inhibitors and an ERK inhibitor are effective against BRAFL514V-mediated resistance. Collectively, our results validate a novel biochemical mechanism of RAF inhibitor resistance mediated by a secondary mutation, emphasizing that, like driver mutations in cancer, the spectrum of mutations that drive resistance to targeted therapy are heterogeneous and perhaps emerge with a lineage-specific prevalence.Significance: In contrast to receptor tyrosine kinases, in which secondary mutations are often responsible for acquired resistance, second-site mutations in BRAF have not been validated in clinically acquired resistance to RAF inhibitors. We demonstrate a secondary mutation in BRAF (V600E/L514V) following progression on dabrafenib and confirm functionally that this mutation is responsible for resistance. Cancer Discov; 8(9); 1130-41. ©2018 AACR.See related commentary by Romano and Kwong, p. 1064This article is highlighted in the In This Issue feature, p. 1047.

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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
BGB3245	BGB3245	6	1
BGB3290	BGB3290	1	0

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
BGB3245		BGB-3245\|BGB 3245	RAF Inhibitor (Pan) 27	BGB3245 inhibits RAF dimer formation, which may lead to inhibition of Erk signaling and cell growth (PMID: 29880583).
BGB3290		BGB-3290\|BGB 3290		BGB3290 inhibits RAF dimer formation, which may lead to inhibition of Erk signaling and cell growth (PMID: 29880583).

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance
BRAF	L514V	missense	gain of function - predicted	BRAF L514V lies within the protein kinase domain of the Braf protein (UniProt.org). L514V is predicted to lead to a gain of Braf function as indicated by moderate increase of Mek and Erk phosphorylation in culture, enhanced dimerization when expressed in cis with BRAF V600E, and is associated with resistance to Raf inhibitors (PMID: 29880583).	Y

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
BRAF L514V BRAF V600E	melanoma	predicted - sensitive	BGB3290	Preclinical - Cell culture	Actionable	In a preclinical study, BGB3290 resulted in similar inhibition of Erk phosphorylation and colony formation in melanoma cells expressing BRAF L514V in cis with V600E and cells expressing BRAF V600E alone in culture (PMID: 29880583).	29880583
BRAF V600E	ganglioglioma	predicted - sensitive	Dabrafenib	Case Reports/Case Series	Actionable	In a clinical case study, Tafinlar (dabrafenib) treatment resulted in partial response 8 weeks after therapy initiation in a pediatric patient with anaplastic ganglioglioma harboring BRAF V600E, but disease progression occurred at 40 weeks due to acquired resistance (PMID: 29880583).	29880583
BRAF L514V	breast cancer	resistant	Dabrafenib	Preclinical - Cell culture	Actionable	In a preclinical study, Tafinlar (dabrafenib) did not inhibit Erk and Mek signaling in breast cancer cells expressing BRAF L514V in culture (PMID: 29880583).	29880583
BRAF L514V BRAF V600E	melanoma	decreased response	Dabrafenib	Preclinical - Cell culture	Actionable	In a preclinical study, melanoma cells expressing BRAF L514V in cis with V600E demonstrated decreased response to Tafinlar (dabrafenib)-induced inhibition of Erk phosphorylation and colony formation compared to cells expressing BRAF V600E in culture (PMID: 29880583).	29880583
BRAF L514V BRAF V600E	melanoma	decreased response	TAK-632	Preclinical - Cell culture	Actionable	In a preclinical study, melanoma cells expressing BRAF L514V in cis with V600E demonstrated decreased response to TAK-632-induced inhibition of Erk phosphorylation and colony formation compared to cells expressing BRAF V600E in culture (PMID: 29880583).	29880583
BRAF L514V BRAF V600E	melanoma	decreased response	Trametinib	Preclinical - Cell culture	Actionable	In a preclinical study, melanoma cells expressing BRAF L514V in cis with V600E demonstrated decreased response to Mekinist (trametinib)-induced inhibition of Erk phosphorylation and colony formation compared to cells expressing BRAF V600E in culture (PMID: 29880583).	29880583
BRAF L514V BRAF V600E	melanoma	decreased response	Vemurafenib	Preclinical - Cell culture	Actionable	In a preclinical study, melanoma cells expressing BRAF L514V in cis with V600E demonstrated decreased response to Zelboraf (vemurafenib)-induced inhibition of Erk phosphorylation and colony formation compared to cells expressing BRAF V600E in culture (PMID: 29880583).	29880583
BRAF L514V BRAF V600E	melanoma	decreased response	PLX8394	Preclinical - Cell culture	Actionable	In a preclinical study, melanoma cells expressing BRAF L514V in cis with V600E demonstrated decreased response to PLX8394-induced inhibition of Erk phosphorylation and colony formation compared to cells expressing BRAF V600E in culture (PMID: 29880583).	29880583
BRAF L514V BRAF V600E	melanoma	predicted - sensitive	BGB3245	Preclinical - Cell culture	Actionable	In a preclinical study, BGB3245 resulted in similar inhibition of Erk phosphorylation and colony formation in melanoma cells expressing BRAF L514V in cis with V600E and cells expressing BRAF V600E alone in culture (PMID: 29880583).	29880583
BRAF L514V BRAF V600E	ganglioglioma	resistant	Dabrafenib	Case Reports/Case Series	Actionable	In a clinical case study, a pediatric patient with anaplastic ganglioglioma harboring BRAF V600E progressed after initial response to Tafinlar (dabrafenib) treatment, and was found to have acquired a BRAF L514V in cis with BRAF V600E, which conferred dabrafenib resistance in culture (PMID: 29880583).	29880583
BRAF L514V BRAF V600E	melanoma	predicted - sensitive	SCH772984	Preclinical - Cell culture	Actionable	In a preclinical study, SCH772984 resulted in similar inhibition of Erk phosphorylation and colony formation in melanoma cells expressing BRAF L514V in cis with V600E and cells expressing BRAF V600E alone in culture (PMID: 29880583).	29880583