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Ref Type

Journal Article

PMID

(32540409)

Authors

Negrao MV, Raymond VM, Lanman RB, Robichaux JP, He J, Nilsson MB, Ng PKS, Amador BE, Roarty EB, Nagy RJ, Banks KC, Zhu VW, Ng C, Chae YK, Clarke JM, Crawford JA, Meric-Bernstam F, Ignatius Ou SH, Gandara DR, Heymach JV, Bivona TG, McCoach CE

Title

Molecular Landscape of BRAF-Mutant NSCLC Reveals an Association Between Clonality and Driver Mutations and Identifies Targetable Non-V600 Driver Mutations.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer	15	10	2020 10	1611-1623	J Thorac Oncol

URL

Abstract Text

Approximately 4% of NSCLC harbor BRAF mutations, and approximately 50% of these are non-V600 mutations. Treatment of tumors harboring non-V600 mutations is challenging because of functional heterogeneity and lack of knowledge regarding their clinical significance and response to targeted agents.We conducted an integrative analysis of BRAF non-V600 mutations using genomic profiles of BRAF-mutant NSCLC from the Guardant360 database. BRAF mutations were categorized by clonality and class (1 and 2: RAS-independent; 3: RAS-dependent). Cell viability assays were performed in Ba/F3 models. Drug screens were performed in NSCLC cell lines.A total of 305 unique BRAF mutations were identified. Missense mutations were most common (276, 90%), and 45% were variants of unknown significance. F468S and N581Y were identified as novel activating mutations. Class 1 to 3 mutations had higher clonality than mutations of unknown class (p < 0.01). Three patients were treated with MEK with or without BRAF inhibitors. Patients harboring G469V and D594G mutations did not respond, whereas a patient with the L597R mutation had a durable response. Trametinib with or without dabrafenib, LXH254, and lifirafenib had more potent inhibition of BRAF non-V600-mutant NSCLC cell lines than other MEK, BRAF, and ERK inhibitors, comparable with the inhibition of BRAF V600E cell line.In BRAF-mutant NSCLC, clonality is higher in known functional mutations and may allow identification of variants of unknown significance that are more likely to be oncogenic drivers. Our data indicate that certain non-V600 mutations are responsive to MEK and BRAF inhibitors. This integration of genomic profiling and drug sensitivity may guide the treatment for BRAF-mutant NSCLC.

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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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Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance
BRAF	N581Y	missense	unknown	BRAF N581Y lies within the protein kinase domain of the Braf protein (UniProt.org). N581Y results in increased cell viability in culture (PMID: 32540409), but has not been fully biochemically characterized and therefore, its effect on Braf protein function is unknown.

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Showing 1 to 26 of 26 entries

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
BRAF D594G	lung adenocarcinoma	no benefit	Trametinib	Case Reports/Case Series	Actionable	In a clinical case study, a lung adenocarcinoma patient harboring BRAF D594G and TP53 H193L demonstrated stable disease for two months when treated with Mekinist (trametinib), but progressed after four months (PMID: 32540409).	32540409
BRAF G469V	lung adenocarcinoma	no benefit	Dabrafenib + Trametinib	Case Reports/Case Series	Actionable	In a clinical case study, a previously treated lung adenocarcinoma patient harboring BRAF G469V demonstrated progression after 9 weeks of treatment with the combination of Mekinist (trametinib) and Tafinlar (dabrafenib) (PMID: 32540409).	32540409
BRAF L597R	lung adenocarcinoma	predicted - sensitive	Dabrafenib + Trametinib	Case Reports/Case Series	Actionable	In a clinical case study, a patient with lung adenocarcinoma harboring BRAF L597R demonstrated clinical improvement and a tumor response at 13 weeks with resolution of hepatic metastasis and mediastinal lymphadenopathy when treated with the combination of Tafinlar (dabrafenib) and Mekinist (trametinib), and at the 12 month follow up remained on treatment, showing no disease progression (PMID: 32540409).	32540409
BRAF G469A	lung adenocarcinoma	resistant	Tovorafenib	Preclinical - Patient cell culture	Actionable	In a preclinical study, cells derived from a lung adenocarcinoma patient harboring BRAF G469A were resistant to treatment with Ojemda (tovorafenib) in culture (PMID: 32540409).	32540409
BRAF G469A	lung adenocarcinoma	sensitive	Dabrafenib + Trametinib	Preclinical - Patient cell culture	Actionable	In a preclinical study, cells derived from a lung adenocarcinoma patient harboring BRAF G469A were sensitive to the combination treatment of Tafinlar (dabrafenib) and Mekinist (trametinib) in culture, demonstrating inhibition of cell growth (PMID: 32540409).	32540409
BRAF G469A	lung adenocarcinoma	resistant	Ravoxertinib	Preclinical - Patient cell culture	Actionable	In a preclinical study, cells derived from a lung adenocarcinoma patient harboring BRAF G469A were resistant to treatment with Ravoxertinib (GDC-0994) in culture (PMID: 32540409).	32540409
BRAF G469A	lung adenocarcinoma	conflicting	Trametinib	Preclinical - Patient cell culture	Actionable	In a preclinical study, cells derived from a lung adenocarcinoma patient harboring BRAF G469A were sensitive to treatment with Mekinist (trametinib) in culture, demonstrating inhibition of cell growth (PMID: 32540409).	32540409
BRAF G469A	lung adenocarcinoma	resistant	Dabrafenib	Preclinical - Patient cell culture	Actionable	In a preclinical study, cells derived from a lung adenocarcinoma patient harboring BRAF G469A were resistant to treatment with Tafinlar (dabrafenib) in culture (PMID: 32540409).	32540409
BRAF G469A	lung adenocarcinoma	sensitive	Lifirafenib	Preclinical - Patient cell culture	Actionable	In a preclinical study, cells derived from a lung adenocarcinoma patient harboring BRAF G469A were sensitive to treatment with Lifirafenib (BGB-283) in culture, demonstrating inhibition of cell growth (PMID: 32540409).	32540409
BRAF G469A	lung adenocarcinoma	resistant	Vemurafenib	Preclinical - Patient cell culture	Actionable	In a preclinical study, cells derived from a lung adenocarcinoma patient harboring BRAF G469A were resistant to treatment with Zelboraf (vemurafenib) in culture (PMID: 32540409).	32540409
BRAF G469A	lung adenocarcinoma	resistant	Ulixertinib	Preclinical - Patient cell culture	Actionable	In a preclinical study, cells derived from a lung adenocarcinoma patient harboring BRAF G469A were resistant to treatment with Ulixertinib (BVD-523) in culture (PMID: 32540409).	32540409
BRAF G469A	lung adenocarcinoma	sensitive	LXH 254	Preclinical - Patient cell culture	Actionable	In a preclinical study, cells derived from a lung adenocarcinoma patient harboring BRAF G469A were sensitive to treatment with LXH 254 in culture, demonstrating inhibition of cell growth (PMID: 32540409).	32540409
BRAF G469A	lung adenocarcinoma	resistant	MK-8353	Preclinical - Patient cell culture	Actionable	In a preclinical study, cells derived from a lung adenocarcinoma patient harboring BRAF G469A were resistant to treatment with MK-8353 in culture (PMID: 32540409).	32540409
BRAF G469A	lung adenocarcinoma	resistant	LY3214996	Preclinical - Patient cell culture	Actionable	In a preclinical study, cells derived from a lung adenocarcinoma patient harboring BRAF G469A were resistant to treatment with LY3214996 in culture (PMID: 32540409).	32540409
BRAF L597V	lung adenocarcinoma	sensitive	Lifirafenib	Preclinical - Patient cell culture	Actionable	In a preclinical study, cells derived from a lung adenocarcinoma patient harboring BRAF L597V were sensitive to treatment with Lifirafenib (BGB-283) in culture, demonstrating inhibition of cell growth (PMID: 32540409).	32540409
BRAF L597V	lung adenocarcinoma	sensitive	Dabrafenib + Trametinib	Preclinical - Patient cell culture	Actionable	In a preclinical study, cells derived from a lung adenocarcinoma patient harboring BRAF L597V were sensitive to the combination treatment of Tafinlar (dabrafenib) and Mekinist (trametinib) in culture, demonstrating inhibition of cell growth (PMID: 32540409).	32540409
BRAF L597V	lung adenocarcinoma	resistant	Encorafenib	Preclinical - Patient cell culture	Actionable	In a preclinical study, cells derived from a lung adenocarcinoma patient harboring BRAF L597V were resistant to treatment with Braftovi (encorafenib) in culture (PMID: 32540409).	32540409
BRAF L597V	lung adenocarcinoma	resistant	Ravoxertinib	Preclinical - Patient cell culture	Actionable	In a preclinical study, cells derived from a lung adenocarcinoma patient harboring BRAF L597V were resistant to treatment with Ravoxertinib (GDC-0994) in culture (PMID: 32540409).	32540409
BRAF L597V	lung adenocarcinoma	resistant	LY3214996	Preclinical - Patient cell culture	Actionable	In a preclinical study, cells derived from a lung adenocarcinoma patient harboring BRAF L597V were resistant to treatment with LY3214996 in culture (PMID: 32540409).	32540409
BRAF L597V	lung adenocarcinoma	sensitive	Trametinib	Preclinical - Patient cell culture	Actionable	In a preclinical study, cells derived from a lung adenocarcinoma patient harboring BRAF L597V were sensitive to treatment with Mekinist (trametinib) in culture, demonstrating inhibition of cell growth (PMID: 32540409).	32540409
BRAF L597V	lung adenocarcinoma	resistant	Dabrafenib	Preclinical - Patient cell culture	Actionable	In a preclinical study, cells derived from a lung adenocarcinoma patient harboring BRAF L597V were resistant to treatment with Tafinlar (dabrafenib) in culture (PMID: 32540409).	32540409
BRAF L597V	lung adenocarcinoma	resistant	Vemurafenib	Preclinical - Patient cell culture	Actionable	In a preclinical study, cells derived from a lung adenocarcinoma patient harboring BRAF L597V were resistant to treatment with Zelboraf (vemurafenib) in culture (PMID: 32540409).	32540409
BRAF L597V	lung adenocarcinoma	resistant	Tovorafenib	Preclinical - Patient cell culture	Actionable	In a preclinical study, cells derived from a lung adenocarcinoma patient harboring BRAF L597V were resistant to treatment with Ojemda (tovorafenib) in culture (PMID: 32540409).	32540409
BRAF L597V	lung adenocarcinoma	resistant	MK-8353	Preclinical - Patient cell culture	Actionable	In a preclinical study, cells derived from a lung adenocarcinoma patient harboring BRAF L597V were resistant to treatment with MK-8353 in culture (PMID: 32540409).	32540409
BRAF L597V	lung adenocarcinoma	resistant	Ulixertinib	Preclinical - Patient cell culture	Actionable	In a preclinical study, cells derived from a lung adenocarcinoma patient harboring BRAF L597V were resistant to treatment with Ulixertinib (BVD-523) in culture (PMID: 32540409).	32540409
BRAF L597V	lung adenocarcinoma	sensitive	LXH 254	Preclinical - Patient cell culture	Actionable	In a preclinical study, cells derived from a lung adenocarcinoma patient harboring BRAF L597V were sensitive to treatment with LXH 254 in culture, demonstrating inhibition of cell growth (PMID: 32540409).	32540409

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