Reference Detail

Ref Type

Journal Article

PMID

(31158244)

Authors

Allen A, Qin ACR, Raj N, Wang J, Uddin S, Yao Z, Tang L, Meyers PA, Taylor BS, Berger MF, Yaeger R, Reidy-Lagunes D, Pratilas CA

Title

Rare BRAF mutations in pancreatic neuroendocrine tumors may predict response to RAF and MEK inhibition.

Journal	Vol	Issue	Date	Pages	Journal Short Title
PloS one	14	6	2019	e0217399	PLoS One

URL

Abstract Text

The clinical significance of BRAF alterations in well-differentiated (WD) metastatic pancreatic neuroendocrine tumor (panNET) is unknown, but BRAF-mutated panNET could represent a subset characterized by an identifiable and clinically actionable driver. Following the identification of two patients with WD metastatic panNET whose tumors harbored BRAF mutations, we queried the MSK-IMPACT series of 80 patients with WD metastatic panNET for additional mutations in BRAF, and in other genes involved in RAS/ RTK/ PI3K signaling pathways. BRAF mutations were identified in six samples (7.5%): two tumors harbored V600E mutations, one tumor each expressed K601E, T599K, and T310I mutations, and one tumor expressed both G596D and E451K BRAF. Few additional actionable driver alterations were identified. To determine the ERK activating capability of four BRAF mutations not previously characterized, mutant constructs were tested in model systems. Biochemical characterization of BRAF mutations revealed both high and low activity mutants. Engineered cells expressing BRAF K601E and V600E were used for in vitro drug testing of RAF and MEK inhibitors currently in clinical use. BRAF K601E demonstrated reduced sensitivity to dabrafenib compared to BRAF V600E, but the combination of RAF plus MEK inhibition was effective in cells expressing this mutation. Herein, we describe the clinical course of a patient with BRAF K601E and a patient with BRAF V600E WD metastatic panNET, and the identification of four mutations in BRAF not previously characterized. The combined clinical and biochemical data support a potential role for RAF and MEK inhibitors, or a combination of these, in a selected panNET population.

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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	E451K	missense	gain of function - predicted	BRAF E451K does not lie within any known functional domains of the Braf protein (UniProt.org). E451K is predicted to lead to a gain of Braf protein function as indicated by intermediate increase of Erk phosphorylation in culture, and is associated with resistance to Raf inhibitors (PMID: 31158244).	Y
BRAF	G596D	missense	unknown	BRAF G596D lies within the protein kinase domain of the Braf protein (UniProt.org). G596D demonstrates decreased Braf kinase activity in one study (PMID: 28783719), but results in increased Erk phosphorylation in another study, and is associated with resistance to Raf inhibitors (PMID: 31158244), and therefore, its effect on Braf protein function is unknown.	Y
BRAF	T310I	missense	gain of function - predicted	BRAF T310I does not lie within any known functional domains of the Braf protein (UniProt.org). T310I is predicted to lead to a gain of Braf protein function as indicated by intermediate increase of Erk phosphorylation in culture, and is associated with resistance to Raf inhibitors (PMID: 31158244).	Y
BRAF	T599K	missense	gain of function - predicted	BRAF T599K lies within the protein kinase domain of the Braf protein (UniProt.org). T599K is predicted to lead to a gain of Braf protein function as demonstrated by increased Erk phosphorylation in culture, and is associated with resistance to Raf inhibitors (PMID: 31158244).	Y

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
BRAF E451K	breast cancer	predicted - resistant	Dabrafenib	Preclinical	Actionable	In a preclinical study, Tafinlar (dabrafenib) treatment resulted in increased Erk phosphorylation in breast cancer cells expressing BRAF E451K in culture (PMID: 31158244).	31158244
BRAF V600E	pancreatic endocrine carcinoma	predicted - sensitive	Vemurafenib	Case Reports/Case Series	Actionable	In a clinical case study, a patient with pancreatic endocrine carcinoma found to harbor BRAF V600E demonstrated stable disease and some tumor shrinkage when treated with Zelboraf (vemurafenib) (PMID: 31158244).	31158244
BRAF G596D	breast cancer	predicted - resistant	Dabrafenib	Preclinical	Actionable	In a preclinical study, Tafinlar (dabrafenib) treatment did not inhibit Erk phosphorylation in breast cancer cells expressing BRAF G596D in culture (PMID: 31158244).	31158244
BRAF T599K	breast cancer	predicted - resistant	Dabrafenib	Preclinical	Actionable	In a preclinical study, Tafinlar (dabrafenib) treatment did not inhibit Erk phosphorylation in breast cancer cells expressing BRAF T599K in culture (PMID: 31158244).	31158244
BRAF K601E	pancreatic endocrine carcinoma	predicted - resistant	Dabrafenib + Trametinib	Case Reports/Case Series	Actionable	In a clinical case study, a patient with a pancreatic neuroendocrine tumor harboring BRAF K601E demonstrated progressive disease when treated with a combination of Tafinlar (dabrafenib) and Mekinist (trametinib) (PMID: 31158244).	31158244
BRAF T310I	breast cancer	predicted - resistant	Dabrafenib	Preclinical	Actionable	In a preclinical study, Tafinlar (dabrafenib) treatment resulted in increased Erk phosphorylation in breast cancer cells expressing BRAF T310I in culture (PMID: 31158244).	31158244
BRAF K601E	pancreatic endocrine carcinoma	predicted - resistant	Trametinib	Case Reports/Case Series	Actionable	In a clinical case study, a patient with a pancreatic neuroendocrine tumor harboring BRAF K601E demonstrated progressive disease when treated with Mekinist (trametinib) (PMID: 31158244).	31158244