Reference Detail

Contact

Missing content? – Request curation!

Request curation for specific Genes, variants, or PubMed publications.

Have questions, comments or suggestions? - Let us know!

Email us at : ckbsupport@jax.org

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 PloS one
Vol 14
Issue 6
Date 2019
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.

Filtering

  • Case insensitive filtering will display rows where any text in any cell matches the filter term
  • Simple literal full or partial string matches
  • Separate multiple filter terms with a spaces, order doesn't matter (a b c and c b a are equivalent )
  • Filtering will only apply to rows that are already loaded on the page, filtering has no impact on query parameters
  • Use quotes to match a longer phrase which contains spaces "mtor c1483f"

Sorting

  • Generally, the default sort order for tables is set to be first column ascending, however, specific tables may set a different default sort order.
  • Click on any column header arrows to sort by that column
  • Hold down the Shift key and click multiple columns to sort by more than one column, be sure to set ascending or descending order for a given column, before moving on to the next column.

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 indicated 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 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 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 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 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 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 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