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Ref Type Journal Article
PMID (18794803)
Authors Smalley KS, Xiao M, Villanueva J, Nguyen TK, Flaherty KT, Letrero R, Van Belle P, Elder DE, Wang Y, Nathanson KL, Herlyn M
Title CRAF inhibition induces apoptosis in melanoma cells with non-V600E BRAF mutations.
Journal Oncogene
Vol 28
Issue 1
Date 2009 Jan 08
URL
Abstract Text Here, we identify a panel of melanoma lines with non-V600E mutations in BRAF. These G469E- and D594G-mutated melanomas were found to exhibit constitutive levels of phospho-extracellular signal-regulated kinase (pERK) and low levels of phospho-mitogen-activated protein kinase/ERK kinase (pMEK) and were resistant to MEK inhibition. Upon treatment with the CRAF inhibitor sorafenib, these lines underwent apoptosis and associated with mitochondrial depolarization and relocalization of apoptosis-inducing factor, whereas the BRAF-V600E-mutated melanomas did not. Studies have shown low-activity mutants of BRAF (G469E/D594G) instead signal through CRAF. Unlike BRAF, CRAF directly regulates apoptosis through mitochondrial localization where it binds to Bcl-2 and phosphorylates BAD. The CRAF inhibitor sorafenib was found to induce a time-dependent reduction in both BAD phosphorylation and Bcl-2 expression in the D594G/G469E lines only. Knockdown of CRAF using a lentiviral shRNA suppressed both Bcl-2 expression and induced apoptosis in the D594G melanoma line but not in a V600E-mutated line. Finally, we showed in a series of xenograft studies that sorafenib was more potent at reducing the growth of tumors with the D594G mutation than those with the V600E mutation. In summary, we have identified a group of melanomas with low-activity BRAF mutations that are reliant upon CRAF-mediated survival activity.

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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 D594G missense unknown BRAF D594G lies within the protein kinase domain of the Braf protein (UniProt.org). D594G has been demonstrated to result in impaired Braf kinase activity, but leads to increased activation of Erk signaling through CRAF in cell culture (PMID: 18794803, PMID: 28783719), has also been shown to result in CRAF activation similar to wild-type Braf but with enhanced dimerization and the ability to bypass autoinhibitory autophosphorylation in in vitro assays (PMID: 31929109), however, has increased transforming ability 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 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 in cell culture (PMID: 28783719, PMID: 33795686), and results in increased cell proliferation and cell viability as compared to wild-type Braf in one of two cell lines (PMID: 29533785), and confers Mek inhibitor resistance in culture (PMID: 18794803), and therefore, its effect on Braf protein function is unknown. Y
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
BRAF D594G melanoma sensitive Sorafenib Preclinical - Cell line xenograft Actionable In a preclinical study, Nexavar (sorafenib) treatment inhibited Erk phosphorylation, reduced growth, and induced mitochondrial depolarization and apoptosis in melanoma cells harboring BRAF D594G in culture, and inhibited tumor growth and induced regression in a cell line xenograft model (PMID: 18794803). 18794803
BRAF G469E melanoma resistant U0126 Preclinical - Cell culture Actionable In a preclinical study, melanoma cells harboring BRAF G469E demonstrated resistance to U0126 treatment in culture (PMID: 18794803). 18794803
BRAF K601E melanoma predicted - sensitive Sorafenib Preclinical - Cell culture Actionable In a preclinical study, Nexavar (sorafenib) treatment induced limited apoptosis and inhibited growth of melanoma cells harboring BRAF K601E in culture (PMID: 18794803). 18794803
BRAF G469E melanoma sensitive Sorafenib Preclinical - Cell culture Actionable In a preclinical study, Nexavar (sorafenib) treatment induced apoptosis and mitochondrial depolarization, and inhibited growth of melanoma cells harboring BRAF G469E in culture (PMID: 18794803). 18794803
BRAF D594G melanoma resistant U0126 Preclinical - Cell culture Actionable In a preclinical study, melanoma cells harboring BRAF D594G demonstrated resistance to U0126 treatment in culture (PMID: 18794803). 18794803
BRAF V600E melanoma predicted - sensitive U0126 Preclinical - Cell culture Actionable In a preclinical study, U0126 treatment inhibited Erk phosphorylation and reduced growth of melanoma cells harboring BRAF V600E in culture (PMID: 18794803). 18794803
BRAF K601E melanoma predicted - sensitive U0126 Preclinical - Cell culture Actionable In a preclinical study, U0126 treatment inhibited growth of melanoma cells harboring BRAF K601E in culture (PMID: 18794803). 18794803