TY - JOUR
T1 - B-Raf inhibition in the clinic
T2 - Present and future
AU - Fiskus, Warren
AU - Mitsiades, Nicholas
N1 - Publisher Copyright:
© 2016 by Annual Reviews.
PY - 2016/1/14
Y1 - 2016/1/14
N2 - Somatic activating mutations in the B-Raf kinase (BRAF mutations) are present in hairy-cell leukemia, cutaneous melanoma, thyroid carcinomas and, less commonly, in ovarian, colon, lung, and other malignancies. These mutations-in particular the most common substitution, V600E-are oncogenic drivers and important therapeutic targets. The development of small-molecule Raf inhibitors allowed rapid translation of basic advances to the clinic. In BRAF-mutant melanomas, orally bioavailable B-Raf inhibitors, such as vemurafenib, achieve dramatic responses initially, but this is followed by rapid emergence of resistance driven by numerous mechanisms and requiring second-generation treatment approaches. In tumors with wild-type B-Raf, vemurafenib paradoxically activates downstream signaling and cell proliferation and is thus contraindicated, highlighting again the importance of genotype-based clinical decision making. These advances were greatly facilitated by the study of biopsied tumor tissue, especially at the time of drug resistance. Combinatorial approaches targeting the Raf pathway hold promise for even more substantial clinical benefits in the future.
AB - Somatic activating mutations in the B-Raf kinase (BRAF mutations) are present in hairy-cell leukemia, cutaneous melanoma, thyroid carcinomas and, less commonly, in ovarian, colon, lung, and other malignancies. These mutations-in particular the most common substitution, V600E-are oncogenic drivers and important therapeutic targets. The development of small-molecule Raf inhibitors allowed rapid translation of basic advances to the clinic. In BRAF-mutant melanomas, orally bioavailable B-Raf inhibitors, such as vemurafenib, achieve dramatic responses initially, but this is followed by rapid emergence of resistance driven by numerous mechanisms and requiring second-generation treatment approaches. In tumors with wild-type B-Raf, vemurafenib paradoxically activates downstream signaling and cell proliferation and is thus contraindicated, highlighting again the importance of genotype-based clinical decision making. These advances were greatly facilitated by the study of biopsied tumor tissue, especially at the time of drug resistance. Combinatorial approaches targeting the Raf pathway hold promise for even more substantial clinical benefits in the future.
KW - Colon cancer
KW - Dabrafenib
KW - Melanoma
KW - Thyroid cancer
KW - Trametinib
KW - Vemurafenib
UR - http://www.scopus.com/inward/record.url?scp=84954502835&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84954502835&partnerID=8YFLogxK
U2 - 10.1146/annurev-med-090514-030732
DO - 10.1146/annurev-med-090514-030732
M3 - Article
C2 - 26768236
AN - SCOPUS:84954502835
SN - 0066-4219
VL - 67
SP - 29
EP - 43
JO - Annual Review of Medicine
JF - Annual Review of Medicine
ER -