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Ref Type Journal Article
PMID (28783719)
Authors Yao Z, Yaeger R, Rodrik-Outmezguine VS, Tao A, Torres NM, Chang MT, Drosten M, Zhao H, Cecchi F, Hembrough T, Michels J, Baumert H, Miles L, Campbell NM, de Stanchina E, Solit DB, Barbacid M, Taylor BS, Rosen N
Title Tumours with class 3 BRAF mutants are sensitive to the inhibition of activated RAS.
Journal Vol Issue Date Pages Journal Short Title
Nature 2017 Aug 02 234-238 Nature
URL
Abstract Text Approximately 200 BRAF mutant alleles have been identified in human tumours. Activating BRAF mutants cause feedback inhibition of GTP-bound RAS, are RAS-independent and signal either as active monomers (class 1) or constitutively active dimers (class 2). Here we characterize a third class of BRAF mutants-those that have impaired kinase activity or are kinase-dead. These mutants are sensitive to ERK-mediated feedback and their activation of signalling is RAS-dependent. The mutants bind more tightly than wild-type BRAF to RAS-GTP, and their binding to and activation of wild-type CRAF is enhanced, leading to increased ERK signalling. The model suggests that dysregulation of signalling by these mutants in tumours requires coexistent mechanisms for maintaining RAS activation despite ERK-dependent feedback. Consistent with this hypothesis, melanomas with these class 3 BRAF mutations also harbour RAS mutations or NF1 deletions. By contrast, in lung and colorectal cancers with class 3 BRAF mutants, RAS is typically activated by receptor tyrosine kinase signalling. These tumours are sensitive to the inhibition of RAS activation by inhibitors of receptor tyrosine kinases. We have thus defined three distinct functional classes of BRAF mutants in human tumours. The mutants activate ERK signalling by different mechanisms that dictate their sensitivity to therapeutic inhibitors of the pathway.

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Molecular Profile Treatment Approach
BRAF G469del MEK inhibitor (Pan)
BRAF G469S MEK inhibitor (Pan)
BRAF G596C MEK inhibitor (Pan)
BRAF K601I MEK inhibitor (Pan)
BRAF G596D MEK inhibitor (Pan)
BRAF Q257R MEK inhibitor (Pan)
BRAF K601E MEK inhibitor (Pan)
BRAF A598_T599insV MEK inhibitor (Pan)
BRAF D594A MEK inhibitor (Pan)
BRAF K601T MEK inhibitor (Pan)
BRAF D594_T599dup MEK inhibitor (Pan)
BRAF G469L MEK inhibitor (Pan)
BRAF L485F MEK inhibitor (Pan)
BRAF F468C MEK inhibitor (Pan)
BRAF L505H MEK inhibitor (Pan)
BRAF T599dup MEK inhibitor (Pan)
BRAF M484_N486del MEK inhibitor (Pan)
BRAF L597V MEK inhibitor (Pan)
BRAF A598V MEK inhibitor (Pan)
BRAF T599R MEK inhibitor (Pan)
BRAF K601N MEK inhibitor (Pan)
BRAF T599I MEK inhibitor (Pan)
BRAF G464V MEK inhibitor (Pan)
BRAF L485_P490del MEK inhibitor (Pan)
BRAF P490_Q494del MEK inhibitor (Pan)
BRAF G596R MEK inhibitor (Pan)
BRAF act mut MEK inhibitor (Pan)
BRAF V600delinsYM MEK inhibitor (Pan)
BRAF D594E MEK inhibitor (Pan)
BRAF L485_P490delinsF MEK inhibitor (Pan)
BRAF G466R MEK inhibitor (Pan)
BRAF V600dup MEK inhibitor (Pan)
BRAF F595L MEK inhibitor (Pan)
BRAF G469V MEK inhibitor (Pan)
BRAF D287H MEK inhibitor (Pan)
BRAF G469R MEK inhibitor (Pan)
BRAF I463S MEK inhibitor (Pan)
BRAF G596V MEK inhibitor (Pan)
BRAF E586K MEK inhibitor (Pan)
BRAF D594N MEK inhibitor (Pan)
BRAF G469A MEK inhibitor (Pan)
BRAF L597P MEK inhibitor (Pan)
BRAF T599_V600insTT MEK inhibitor (Pan)
BRAF L597S MEK inhibitor (Pan)
BRAF N486_T491delinsK MEK inhibitor (Pan)
BRAF K499E MEK inhibitor (Pan)
BRAF G466V MEK inhibitor (Pan)
BRAF G464R MEK inhibitor (Pan)
BRAF T599_V600insEAT MEK inhibitor (Pan)
BRAF T599_V600insETT MEK inhibitor (Pan)
BRAF V504_R506dup MEK inhibitor (Pan)
BRAF K601Q MEK inhibitor (Pan)
BRAF G464E MEK inhibitor (Pan)
BRAF L597Q MEK inhibitor (Pan)
BRAF A598_T599insARC MEK inhibitor (Pan)
BRAF S467A MEK inhibitor (Pan)
BRAF A728V MEK inhibitor (Pan)
BRAF F247L MEK inhibitor (Pan)
BRAF L485_P490delinsY MEK inhibitor (Pan)
BRAF V487_P492delinsA MEK inhibitor (Pan)
BRAF D594Y MEK inhibitor (Pan)
BRAF V600_K601delinsE MEK inhibitor (Pan)
BRAF L597R MEK inhibitor (Pan)
BRAF V471F MEK inhibitor (Pan)
BRAF T488_Q493delinsK MEK inhibitor (Pan)
BRAF T488_P492del MEK inhibitor (Pan)
BRAF D594H MEK inhibitor (Pan)
BRAF R347* MEK inhibitor (Pan)
BRAF N486_P490del MEK inhibitor (Pan)
BRAF N486_L495del MEK inhibitor (Pan)
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 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 class 3 unknown loss of function BRAF Class 3 variants are BRAF variants that demonstrate low or no BRAF kinase activity, but activate downstream signaling through CRAF activation, in a dimer-dependent, RAS-dependent manner (PMID: 28783719).
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 D594A missense loss of function BRAF D594A lies within the protein kinase domain of the Braf protein (UniProt.org). D594A results in a lack of Braf kinase activity (PMID: 20141835, PMID: 20978199, PMID: 28783719), promotes aneupolidy (PMID: 20978199), and in one of two cell lines demonstrated decreased transformation ability compared to wild-type Braf in culture (PMID: 29533785), but leads to activation of Mek and Erk through cooperation with activated RAS and transactivation of CRAF in cell culture and mouse models (PMID: 20141835, PMID: 20978199, PMID: 28783719).
BRAF D594E missense loss of function BRAF D594E lies within the protein kinase domain of the Braf protein (UniProt.org). D594E results in impaired Braf kinase activity, however, results in increased Mek and Erk phosphorylation in the presence of CRAF in cell culture (PMID: 28783719).
BRAF D594G missense loss of function - predicted BRAF D594G lies within the protein kinase domain of the Braf protein (UniProt.org). D594G demonstrates increased transforming ability in one of two cell lines in culture (PMID: 29533785), however, results in impaired Braf kinase activity, but leads to increased activation of Erk signaling through Craf in cell culture (PMID: 18794803, PMID: 28783719), and also demonstrates Craf activation similar to wild-type Braf, but with enhanced dimerization and the ability to bypass autoinhibitory autophosphorylation in in vitro assays (PMID: 31929109), and confers Mek inhibitor resistance in culture (PMID: 18794803), and therefore, is predicted to lead to a loss of Braf protein function. Y
BRAF D594H missense loss of function - predicted BRAF D594H lies within the protein kinase domain of the Braf protein (UniProt.org). D594H leads to Ras-dependent activation of Erk signaling through CRAF but results in a loss of Braf kinase activity (PMID: 28783719) and demonstrates decreased transforming activity compared to wild-type Braf in one of two cell lines in culture (PMID: 29533785), and therefore, is predicted to lead to a loss of Braf protein function.
BRAF D594N missense loss of function - predicted BRAF D594N lies within the protein kinase domain of the Braf protein (UniProt.org). D594N leads to activation of Erk signaling through CRAF but results in impaired Braf kinase activity in cell culture (PMID: 28783719) and decreased transformation ability compared to wild-type Braf in one of two cell lines in culture (PMID: 29533785), and therefore, is predicted to lead to a loss of Braf protein function.
BRAF F595L missense loss of function BRAF F595L lies within the protein kinase domain of the Braf protein (UniProt.org). F595L results in reduced Braf kinase activity (PMID: 28783719, PMID: 15035987), but works cooperatively with oncogenic Ras to activate MEK/ERK signaling, and is transforming in cell culture (PMID: 15035987, PMID: 26582644, PMID: 29533785).
BRAF G466A missense unknown BRAF G466A (also reported as G465A) lies within the protein kinase domain of the Braf protein (UniProt.org). The functional effect of G466A (also reported as G465A) is conflicting as it has been characterized both as having intermediate Braf kinase activity (PMID: 15035987) and low Braf kinase activity (PMID: 28783719), leads to Ras-dependent activation of downstream Erk in cell culture (PMID: 28783719), and in one of two cell lines increased cell proliferation and cell viability compared to wild-type Braf (PMID: 29533785).
BRAF G466V missense loss of function BRAF G466V lies within the protein kinase domain of the Braf protein (UniProt.org). G466V results in impaired Braf kinase activity, but paradoxically activates MEK and ERK through transactivation of CRAF in cell culture (PMID: 22649091, PMID: 28783719), and in one of two cell lines, G466V decreased cell proliferation and cell viability as compared to wild-type Braf (PMID: 29533785).
BRAF G469E missense unknown BRAF G469E is a hotspot mutation that lies within the protein kinase domain of the Braf protein (UniProt.org). G469E results in decreased Braf kinase activity (PMID: 28783719, PMID: 15035987), but leads to Ras-dependent activation of Erk signaling (PMID: 28783719, PMID: 33795686), and results in increased cell proliferation and cell viability in one of two cell lines in culture (PMID: 29533785), and confers Mek inhibitor resistance in culture (PMID: 18794803), and therefore, its effect on Braf protein function is unknown. Y
BRAF G469R missense gain of function - predicted BRAF G469R is a hotspot mutation within the protein kinase domain of the Braf protein (UniProt.org). G469R demonstrates intermediate BRAF kinase activity (PMID: 28783719), results in constitutive ERK activation in cell culture (PMID: 24920063), and in one of two cell lines leads to increased cell proliferation and cell viability compared to wild-type Braf (PMID: 29533785), and therefore, is predicted to lead to a gain of Braf protein function.
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 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 G596R missense loss of function - predicted BRAF G596R lies within the protein kinase domain of the Braf protein (UniProt.org). G596R results in activation of Erk in the presence of CRAF (PMID: 19735675, PMID: 28783719, PMID: 18697864) and in another study demonstrates similar cell proliferation and viability levels to wild-type Braf (PMID: 29533785), but results in impaired Braf kinase activity and decreased Mek and Erk phosphorylation, including in the presence of BRAF V600E, is not transforming in culture, and does not promote tumor formation in mouse models (PMID: 19735675, PMID: 28783719), and therefore, is predicted to lead to a loss of Braf protein function.
BRAF K601E missense gain of function BRAF K601E lies within the activation segment in the kinase domain of the Braf protein (PMID: 15343278). K601E results in increased Braf kinase activity and downstream activation of MEK and ERK in cell culture (PMID: 22798288, PMID: 28783719, PMID: 32059434), and induces cell proliferation and cell viability in culture (PMID: 29533785, PMID: 18697864).
BRAF K601T missense gain of function - predicted BRAF K601T lies within the activation segment in the kinase domain of the Braf protein (PMID: 15343278). K601T results in increased Braf kinase activity in cell culture (PMID: 28783719), and in one of two cell lines increased cell proliferation and cell viability compared to wild-type Braf (PMID: 29533785), and therefore, is predicted to lead to a gain of Braf protein function.
BRAF N581I missense unknown BRAF N581I lies within the protein kinase domain of the Braf protein (UniProt.org). N581I results in low Braf kinase activity and Ras-dependent activation of Erk signaling in cell culture (PMID: 28783719), however, also results in increased transformation ability compared to wild-type Braf in culture (PMID: 29533785), and therefore, its effect on Braf protein function is unknown.
BRAF N581S missense unknown BRAF N581S lies within the protein kinase domain of the Braf protein (UniProt.org). N581S has been identified as a secondary resistance mutation (PMID: 32553555), and results in intermediate Braf kinase activity (PMID: 15035987) as well as low Braf kinase activity (PMID: 28783719), and results in Ras-dependent activation of Erk signaling in cell culture (PMID: 28783719), however in another study, demonstrates increased transformation ability in one of two different cell lines compared to wild-type Braf (PMID: 29533785), and therefore, its effect on Braf protein function is unknown. Y
BRAF S467L missense loss of function - predicted BRAF S467L lies within the protein kinase domain of the Braf protein (UniProt.org). S467L results in impaired Braf kinase activity, but leads to Ras-dependent activation of Erk in cell culture (PMID: 28783719) and increased cell proliferation and cell viability in two different cell lines (PMID: 29533785), and therefore, is predicted to lead to a loss of Braf protein function.
BRAF T529M missense unknown BRAF T529M lies within the protein kinase domain of the Braf protein (UniProt.org). T529M has been demonstrated to confer resistance to Raf inhibitors (PMID: 20538618, PMID: 28783719, PMID: 31453322), but has not been biochemically characterized and therefore, its effect on Braf protein function is unknown (PubMed, Dec 2023). Y
BRAF V459L missense unknown BRAF V459L lies within the protein kinase domain of the Braf protein (UniProt.org). V459L results in impaired Braf kinase activity and leads to Ras-dependent activation of Erk in culture (PMID: 28783719), however, in two different cell lines, induces similar proliferation and viability as compared to wild-type Braf in culture (PMID: 29533785), and therefore, its effect on Braf protein function is unknown.
BRAF V600M missense gain of function - predicted BRAF V600M (previously reported as V599) lies within the activation segment of the kinase domain of the Braf protein (PMID: 15035987). V600M results in intermediate Braf kinase activity in cell culture (PMID: 28783719), and in one of two cell lines increased cell proliferation and cell viability compared to wild-type Braf (PMID: 29533785), and therefore, is predicted to lead to a gain of Braf protein function.
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
BRAF G466V colorectal cancer predicted - resistant Vemurafenib Preclinical - Pdx Actionable In a preclinical study, Zelboraf (vemurafenib) did not inhibit ERK signaling or tumor growth in a colorectal cancer patient-derived xenograft (PDX) model harboring BRAF G466V, and wild-type RAS and NF1 (PMID: 28783719). 28783719
BRAF G596R colorectal cancer sensitive Trametinib Preclinical - Cell culture Actionable In a preclinical study, Mekinist (trametinib) reduced Erk signaling and inhibited proliferation of a colorectal cancer cell line harboring BRAF G596R in culture (PMID: 28783719). 28783719
BRAF G466V colorectal cancer not predictive Irinotecan + Panitumumab Case Reports/Case Series Actionable In a clinical case study, a patient with metastatic colorectal cancer harboring BRAF G466V, and with wild-type RAS and NF1, demonstrated tumor regression following treatment with Vectibix (panitumumab) plus Camptosar (irinotecan) (PMID: 28783719). 28783719
BRAF G596R colorectal cancer resistant Vemurafenib Preclinical - Cell culture Actionable In a preclinical study, Zelboraf (vemurafenib) did not reduce activation of Erk and Mek in a colorectal cancer cell line harboring BRAF G596R in culture (PMID: 28783719). 28783719
BRAF D594N Advanced Solid Tumor predicted - resistant Vemurafenib Preclinical - Cell culture Actionable In a preclinical study, Zelboraf (vemurafenib) did not reduce activation of Mek in transformed cells expressing BRAF D594N in culture (PMID: 28783719). 28783719
BRAF G466V colorectal cancer sensitive Cetuximab Preclinical - Pdx Actionable In a preclinical study, treatment with Erbitux (cetuximab) reduced ERK signaling and resulted in tumor regression in a colorectal cancer patient-derived xenograft (PDX) model harboring BRAF G466V, and wild-type RAS and NF1 (PMID: 28783719). 28783719
BRAF G466V lung non-small cell carcinoma sensitive Trametinib Preclinical - Cell culture Actionable In a preclinical study, Mekinist (trametinib) reduced ERK signaling and inhibited proliferation of non-small cell lung cancer cell lines harboring BRAF G466V in culture (PMID: 28783719). 28783719
BRAF D594G melanoma sensitive Trametinib Preclinical - Cell culture Actionable In a preclinical study, Mekinist (trametinib) reduced ERK signaling and inhibited proliferation of a melanoma cell line harboring BRAF D594G in culture (PMID: 28783719). 28783719
BRAF G466E HRAS Q61K melanoma sensitive Trametinib Preclinical - Cell culture Actionable In a preclinical study, Mekinist (trametinib) reduced ERK signaling and inhibited proliferation of a melanoma cell line harboring BRAF G466E and HRAS Q61K in culture (PMID: 28783719). 28783719
BRAF G466V NRAS Q61K lung non-small cell carcinoma sensitive Trametinib Preclinical - Cell culture Actionable In a preclinical study, Mekinist (trametinib) growth of a non-small cell lung cancer cell line harboring BRAF G466V and expressing NRAS Q61K in culture (PMID: 28783719). 28783719
BRAF G466V colorectal cancer sensitive Trametinib Preclinical - Pdx Actionable In a preclinical study, treatment with Mekinist (trametinib) delayed tumor growth in a colorectal cancer patient-derived xenograft (PDX) model harboring BRAF G466V, and wild-type RAS and NF1 (PMID: 28783719). 28783719