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|Ref Type||Journal Article|
|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||Pigment cell & melanoma research|
|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.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|PLX8394||PLX 8394|PLX-8394|FORE8394|FORE-8394|FORE 8394||BRAF Inhibitor 21 CRAF Inhibitor 11||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|