Reference Detail

Ref Type

Journal Article

PMID

(24283590)

Authors

Choi J, Landrette SF, Wang T, Evans P, Bacchiocchi A, Bjornson R, Cheng E, Stiegler AL, Gathiaka S, Acevedo O, Boggon TJ, Krauthammer M, Halaban R, Xu T

Title

Identification of PLX4032-resistance mechanisms and implications for novel RAF inhibitors.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Pigment cell & melanoma research	27	2	2014 Mar	253-62	Pigment Cell Melanoma Res

URL

Abstract Text

BRAF inhibitors improve melanoma patient survival, but resistance invariably develops. Here we report the discovery of a novel BRAF mutation that confers resistance to PLX4032 employing whole-exome sequencing of drug-resistant BRAF(V600K) melanoma cells. We further describe a new screening approach, a genome-wide piggyBac mutagenesis screen that revealed clinically relevant aberrations (N-terminal BRAF truncations and CRAF overexpression). The novel BRAF mutation, a Leu505 to His substitution (BRAF(L505H) ), is the first resistance-conferring second-site mutation identified in BRAF mutant cells. The mutation replaces a small nonpolar amino acid at the BRAF-PLX4032 interface with a larger polar residue. Moreover, we show that BRAF(L505H) , found in human prostate cancer, is itself a MAPK-activating, PLX4032-resistant oncogenic mutation. Lastly, we demonstrate that the PLX4032-resistant melanoma cells are sensitive to novel, next-generation BRAF inhibitors, especially the 'paradox-blocker' PLX8394, supporting its use in clinical trials for treatment of melanoma patients with BRAF-mutations.

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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
PLX8394	PLX8394	25	3

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
PLX8394		PLX 8394\|PLX-8394\|FORE8394\|FORE-8394\|FORE 8394	BRAF Inhibitor 25 CRAF Inhibitor 12	PLX8394 is a RAF inhibitor that inhibits wild-type and mutant BRAF, as well as CRAF, and does not paradoxically activate MAPK signaling, potentially resulting in decreased proliferation of BRAF-mutant tumor cells (PMID: 26466569, PMID: 24283590, PMID: 28659148, PMID: 30559419).

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance
BRAF	L505H	missense	gain of function	BRAF L505H lies within the protein kinase domain of the Braf protein (UniProt.org). L505H confers a gain of function to the Braf protein resulting in MEK/ERK activation and oncogenic transformation in cultured cells, and is associated with resistance to RAF inhibitors (PMID: 24283590).	Y

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
BRAF L505H	melanoma	resistant	Vemurafenib	Preclinical	Actionable	In a preclinical study, melanoma cells expressing BRAF L505H were resistant to Zelboraf (vemurafenib) (PMID: 24283590).	24283590