To all our CKB CORE users, don’t miss the latest new features now available! Register for a free CORE account here and then login for access. Feel free to contact us at ckbsupport@genomenon.com if you have any questions!

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@genomenon.com

Ref Type Journal Article
PMID (26343582)
Authors Yao Z, Torres NM, Tao A, Gao Y, Luo L, Li Q, de Stanchina E, Abdel-Wahab O, Solit DB, Poulikakos PI, Rosen N
Title BRAF Mutants Evade ERK-Dependent Feedback by Different Mechanisms that Determine Their Sensitivity to Pharmacologic Inhibition.
Journal Vol Issue Date Pages Journal Short Title
Cancer cell 28 3 2015 Sep 14 370-83 Cancer Cell
URL
Abstract Text ERK signaling requires RAS-induced RAF dimerization and is limited by feedback. Activated BRAF mutants evade feedback inhibition of RAS by either of two mechanisms. BRAF V600 mutants are activated monomers when RAS activity is low; all other activating BRAF mutants function as constitutive RAS-independent dimers. RAF inhibitors effectively inhibit mutant monomers, but not dimers; their binding to one site in the dimer significantly reduces their affinity for the second. Tumors with non-V600E BRAF mutants are insensitive to these drugs, and increased expression of BRAF V600E dimers causes acquired resistance. A compound that equally inhibits both sites of mutant RAF dimers inhibits tumors driven by either class of mutants or those BRAF V600E tumors with dimer-dependent acquired resistance to monomer-specific inhibitors.

Filtering

  • Case insensitive filtering will display rows if any text in any cell matches the filter term
  • Use simple literal full or partial string matches
  • Separate multiple filter terms with a space. Any order may be used (i. e. 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 on a longer phrase with spaces (i.e. "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
BGB659 ML 786 RAF Inhibitor (Pan) 28 BGB659 is a pan-RAF inhibitor that results in inhibition of MEK/ERK signaling generated by either RAF dimers or RAF monomers and thus, prevents cell proliferation (PMID: 26343582).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
BRAF class 1 unknown gain of function BRAF Class 1 variants are BRAF variants that activate BRAF and downstream signaling in a dimer-independent, RAS-independent manner (PMID: 28783719, PMID: 26343582).
BRAF class 2 unknown gain of function BRAF Class 2 variants are BRAF variants that activate BRAF and downstream signaling in a dimer-dependent, RAS-independent manner (PMID: 28783719, PMID: 26343582).
BRAF D287H missense loss of function BRAF D287H does not lie within any known functional domains of the Braf protein (UniProt.org). D287H results in impaired Braf kinase activity, but leads to Ras-dependent activation of Erk in cell culture (PMID: 26343582, PMID: 28783719).
BRAF G464V missense gain of function BRAF G464V (also reported as G463V) lies within the protein kinase domain of the Braf protein (UniProt.org). G464V results in increased Braf kinase activity and increased downstream Mek and Erk activation (PMID: 12068308, PMID: 26343582), and in one of two cell lines, increased cell proliferation and viability compared to wild-type Braf in culture (PMID: 29533785).
BRAF G469V missense gain of function BRAF G469V is a hotspot mutation within the protein kinase domain of the Braf protein (UniProt.org). G469V results in increased Braf kinase activity and activation of downstream MEK and ERK in cell culture (PMID: 28947956, PMID: 26343582, PMID: 28783719), and in one of two cell lines, increased cell proliferation and cell viability compared to wild-type Braf (PMID: 29533785).
BRAF L597R missense gain of function BRAF L597R lies within the protein kinase domain of the Braf protein (UniProt.org). L597R results in activation of Braf as indicated by increased phosphorylation of Mek and Erk in cell culture (PMID: 22798288, PMID: 26343582), is associated with Erk activation in a patient tumor sample (PMID: 23715574), and in one of two cell lines, increased cell proliferation and cell viability compared to wild-type Braf (PMID: 29533785).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
BRAF G469V Advanced Solid Tumor resistant Vemurafenib Preclinical - Cell culture Actionable In a preclinical study, Zelboraf (vemurafenib) did not inhibit MEK and ERK activation in transformed cells over expressing the constitutively dimerized BRAF G469V (PMID: 26343582). 26343582
BRAF G464R Advanced Solid Tumor resistant Vemurafenib Preclinical - Cell culture Actionable In a preclinical study, Zelboraf (vemurafenib) did not inhibit MEK and ERK activation in transformed cells over expressing the constitutively dimerized BRAF G464R (PMID: 26343582). 26343582
BRAF K601T Advanced Solid Tumor resistant Vemurafenib Preclinical - Cell culture Actionable In a preclinical study, Zelboraf (vemurafenib) did not inhibit MEK and ERK activation in transformed cells over expressing the constitutively dimerized BRAF K601T (PMID: 26343582). 26343582
BRAF K601N Advanced Solid Tumor resistant Vemurafenib Preclinical - Cell culture Actionable In a preclinical study, Zelboraf (vemurafenib) did not inhibit MEK and ERK activation in transformed cells over expressing the constitutively dimerized BRAF K601N (PMID: 26343582). 26343582
BRAF L597V Advanced Solid Tumor resistant Vemurafenib Preclinical - Cell culture Actionable In a preclinical study, Zelboraf (vemurafenib) did not inhibit MEK and ERK activation in transformed cells over expressing the constitutively dimerized BRAF L597V (PMID: 26343582). 26343582
BRAF L597Q Advanced Solid Tumor resistant Vemurafenib Preclinical - Cell culture Actionable In a preclinical study, Zelboraf (vemurafenib) did not inhibit MEK and ERK activation in transformed cells over expressing the constitutively dimerized BRAF L597Q (PMID: 26343582). 26343582
BRAF K601E Advanced Solid Tumor conflicting Vemurafenib Preclinical - Cell culture Actionable In a preclinical study, Zelboraf (vemurafenib) did not inhibit MEK and ERK activation in transformed cells over expressing the constitutively dimerized BRAF K601E (PMID: 26343582). 26343582
BRAF G469A Advanced Solid Tumor resistant Vemurafenib Preclinical - Cell culture Actionable In a preclinical study, Zelboraf (vemurafenib) did not inhibit MEK and ERK activation in transformed cells over expressing the constitutively dimerized BRAF G469A (PMID: 26343582). 26343582
BRAF G464V Advanced Solid Tumor resistant Vemurafenib Preclinical - Cell culture Actionable In a preclinical study, Zelboraf (vemurafenib) did not inhibit MEK and ERK activation in transformed cells over expressing the constitutively dimerized BRAF G464V (PMID: 26343582). 26343582
BRAF G464E Advanced Solid Tumor resistant Vemurafenib Preclinical - Cell culture Actionable In a preclinical study, Zelboraf (vemurafenib) did not inhibit MEK and ERK activation in transformed cells over expressing the constitutively dimerized BRAF G464E (PMID: 26343582). 26343582