Oncogenic BRAF is required for tumor growth and maintenance in melanoma models.
The usual paradigm for developing kinase inhibitors in oncology is to use a high-affinity proof-of-concept inhibitor with acceptable metabolic properties for key target validation experiments. This approach requires substantial medicinal chemistry and can be confounded by drug toxicity and off-target activities of the test molecule. As a better alternative, we have developed inducible short-hairpin RNA xenograft models to examine the in vivo efficacy of inhibiting oncogenic BRAF. Our results show that tumor regression resulting from BRAF suppression is inducible, reversible, and tightly regulated in these models. Analysis of regressing tumors showed the primary mechanism of action for BRAF to be increased tumor cell proliferation and survival. In a metastatic melanoma model, conditional BRAF suppression slowed systemic tumor growth as determined by in vivo bioluminescence imaging. Taken together, gain-of-function BRAF signaling is strongly associated with in vivo tumorigenicity, confirming BRAF as an important target for small-molecule and RNA interference-based therapeutics.
Hoeflich
Klaus P
KP
Department of Molecular Biology, Genentech Inc., 1 DNA Way MS224, South San Francisco, CA 94080, USA.
Gray
Daniel C
DC
Eby
Michael T
MT
Tien
Janet Y
JY
Wong
Leo
L
Bower
Janeko
J
Gogineni
Alvin
A
Zha
Jiping
J
Cole
Mary J
MJ
Stern
Howard M
HM
Murray
Lesley J
LJ
Davis
David P
DP
Seshagiri
Somasekar
S
D000818:Animals; D049109:Cell Proliferation; D004195:Disease Models, Animal; D015536:Down-Regulation; D005260:Female; D006801:Humans; D008545:Melanoma / Q000235:genetics / Q000473:pathology*; D051379:Mice; D008819:Mice, Nude; D009362:Neoplasm Metastasis; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology*; D034622:RNA Interference; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000235:genetics / Q000473:pathology*; D014183:Transplantation, Heterologous
C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf