Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant melanoma.
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.
Bollag
Gideon
G
Plexxikon Inc., 91 Bolivar Drive, Berkeley, California 94710, USA. gbollag@plexxikon.com
Hirth
Peter
P
Tsai
James
J
Zhang
Jiazhong
J
Ibrahim
Prabha N
PN
Cho
Hanna
H
Spevak
Wayne
W
Zhang
Chao
C
Zhang
Ying
Y
Habets
Gaston
G
Burton
Elizabeth A
EA
Wong
Bernice
B
Tsang
Garson
G
West
Brian L
BL
Powell
Ben
B
Shellooe
Rafe
R
Marimuthu
Adhirai
A
Nguyen
Hoa
H
Zhang
Kam Y J
KY
Artis
Dean R
DR
Schlessinger
Joseph
J
Su
Fei
F
Higgins
Brian
B
Iyer
Raman
R
D'Andrea
Kurt
K
Koehler
Astrid
A
Stumm
Michael
M
Lin
Paul S
PS
Lee
Richard J
RJ
Grippo
Joseph
J
Puzanov
Igor
I
Kim
Kevin B
KB
Ribas
Antoni
A
McArthur
Grant A
GA
Sosman
Jeffrey A
JA
Chapman
Paul B
PB
Flaherty
Keith T
KT
Xu
Xiaowei
X
Nathanson
Katherine L
KL
Nolop
Keith
K
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
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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