title: Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant melanoma.
abstract: B-RAF is the most frequently mutated protein kinase in human cancers. The finding that oncogenic mutations in BRAF are common in melanoma, followed by the demonstration that these tumours are dependent on the RAF/MEK/ERK pathway, offered hope that inhibition of B-RAF kinase activity could benefit melanoma patients. Herein, we describe the structure-guided discovery of PLX4032 (RG7204), a potent inhibitor of oncogenic B-RAF kinase activity. Preclinical experiments demonstrated that PLX4032 selectively blocked the RAF/MEK/ERK pathway in BRAF mutant cells and caused regression of BRAF mutant xenografts. Toxicology studies confirmed a wide safety margin consistent with the high degree of selectivity, enabling Phase 1 clinical trials using a crystalline formulation of PLX4032 (ref. 5). In a subset of melanoma patients, pathway inhibition was monitored in paired biopsy specimens collected before treatment initiation and following two weeks of treatment. This analysis revealed substantial inhibition of ERK phosphorylation, yet clinical evaluation did not show tumour regressions. At higher drug exposures afforded by a new amorphous drug formulation, greater than 80% inhibition of ERK phosphorylation in the tumours of patients correlated with clinical response. Indeed, the Phase 1 clinical data revealed a remarkably high 81% response rate in metastatic melanoma patients treated at an oral dose of 960 mg twice daily. These data demonstrate that BRAF-mutant melanomas are highly dependent on B-RAF kinase activity.
authors.affiliation: Plexxikon Inc., 91 Bolivar Drive, Berkeley, California 94710, USA. gbollag@plexxikon.com
authors.forename: Gideon
authors.initials: G
authors.lastname: Bollag
authors.forename: Peter
authors.initials: P
authors.lastname: Hirth
authors.forename: James
authors.initials: J
authors.lastname: Tsai
authors.forename: Jiazhong
authors.initials: J
authors.lastname: Zhang
authors.forename: Prabha N
authors.initials: PN
authors.lastname: Ibrahim
authors.forename: Hanna
authors.initials: H
authors.lastname: Cho
authors.forename: Wayne
authors.initials: W
authors.lastname: Spevak
authors.forename: Chao
authors.initials: C
authors.lastname: Zhang
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhang
authors.forename: Gaston
authors.initials: G
authors.lastname: Habets
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Burton
authors.forename: Bernice
authors.initials: B
authors.lastname: Wong
authors.forename: Garson
authors.initials: G
authors.lastname: Tsang
authors.forename: Brian L
authors.initials: BL
authors.lastname: West
authors.forename: Ben
authors.initials: B
authors.lastname: Powell
authors.forename: Rafe
authors.initials: R
authors.lastname: Shellooe
authors.forename: Adhirai
authors.initials: A
authors.lastname: Marimuthu
authors.forename: Hoa
authors.initials: H
authors.lastname: Nguyen
authors.forename: Kam Y J
authors.initials: KY
authors.lastname: Zhang
authors.forename: Dean R
authors.initials: DR
authors.lastname: Artis
authors.forename: Joseph
authors.initials: J
authors.lastname: Schlessinger
authors.forename: Fei
authors.initials: F
authors.lastname: Su
authors.forename: Brian
authors.initials: B
authors.lastname: Higgins
authors.forename: Raman
authors.initials: R
authors.lastname: Iyer
authors.forename: Kurt
authors.initials: K
authors.lastname: D'Andrea
authors.forename: Astrid
authors.initials: A
authors.lastname: Koehler
authors.forename: Michael
authors.initials: M
authors.lastname: Stumm
authors.forename: Paul S
authors.initials: PS
authors.lastname: Lin
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Lee
authors.forename: Joseph
authors.initials: J
authors.lastname: Grippo
authors.forename: Igor
authors.initials: I
authors.lastname: Puzanov
authors.forename: Kevin B
authors.initials: KB
authors.lastname: Kim
authors.forename: Antoni
authors.initials: A
authors.lastname: Ribas
authors.forename: Grant A
authors.initials: GA
authors.lastname: McArthur
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Sosman
authors.forename: Paul B
authors.initials: PB
authors.lastname: Chapman
authors.forename: Keith T
authors.initials: KT
authors.lastname: Flaherty
authors.forename: Xiaowei
authors.initials: X
authors.lastname: Xu
authors.forename: Katherine L
authors.initials: KL
authors.lastname: Nathanson
authors.forename: Keith
authors.initials: K
authors.lastname: Nolop
mesh_terms: D000483:Alleles; D000818:Animals; D004285:Dogs; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000008:administration & dosage / Q000009:adverse effects / Q000737:chemistry / Q000627:therapeutic use*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008252:Macaca fascicularis; D008545:Melanoma / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D008958:Models, Molecular; D050505:Mutant Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D009362:Neoplasm Metastasis; D010766:Phosphorylation / Q000187:drug effects; D049268:Positron-Emission Tomography; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D051381:Rats; D013379:Substrate Specificity; D013449:Sulfonamides / Q000008:administration & dosage / Q000009:adverse effects / Q000737:chemistry / Q000627:therapeutic use*; D000077484:Vemurafenib; D023041:Xenograft Model Antitumor Assays
chemical_list: D007211:Indoles; D050505:Mutant Proteins; D013449:Sulfonamides; D000077484:Vemurafenib; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D048049:Extracellular Signal-Regulated MAP Kinases
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