Reference Detail

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	Vol	Issue	Date	Pages	Journal Short Title
Oncogene	28	1	2009 Jan 08	85-94	Oncogene

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	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	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

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
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
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	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 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 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 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 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