BRAF(L597) mutations in melanoma are associated with sensitivity to MEK inhibitors.
Kinase inhibitors are accepted treatment for metastatic melanomas that harbor specific driver mutations in BRAF or KIT, but only 40% to 50% of cases are positive. To uncover other potential targetable mutations, we conducted whole-genome sequencing of a highly aggressive BRAF (V600) and KIT (W557, V559, L576, K642, and D816) wild-type melanoma. Surprisingly, we found a somatic BRAF(L597R) mutation in exon 15. Analysis of BRAF exon 15 in 49 tumors negative for BRAF(V600) mutations as well as driver mutations in KIT, NRAS, GNAQ, and GNA11, showed that two (4%) harbored L597 mutations and another two involved BRAF D594 and K601 mutations. In vitro signaling induced by L597R/S/Q mutants was suppressed by mitogen-activated protein (MAP)/extracellular signal-regulated kinase (ERK) kinase (MEK) inhibition. A patient with BRAF(L597S) mutant metastatic melanoma responded significantly to treatment with the MEK inhibitor, TAK-733. Collectively, these data show clinical significance to BRAF(L597) mutations in melanoma.


CONCLUSIONS
This study shows that cells harboring BRAF(L597R) mutants are sensitive to MEK inhibitor treatment, providing a rationale for routine screening and therapy of BRAF(L597R)-mutant melanoma.
Vanderbilt-Ingram Cancer Center, Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA.
Kimberly Brown
KB
Dahlman
Junfeng
J
Xia
Katherine
K
Hutchinson
Charles
C
Ng
Donald
D
Hucks
Peilin
P
Jia
Mohammad
M
Atefi
Zengliu
Z
Su
Suzanne
S
Branch
Pamela L
PL
Lyle
Donna J
DJ
Hicks
Viviana
V
Bozon
John A
JA
Glaspy
Neal
N
Rosen
David B
DB
Solit
James L
JL
Netterville
Cindy L
CL
Vnencak-Jones
Jeffrey A
JA
Sosman
Antoni
A
Ribas
Zhongming
Z
Zhao
William
W
Pao
D000368:Aged; D045744:Cell Line, Tumor; D015894:Genome, Human; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D011728:Pyridones / Q000627:therapeutic use*; D011744:Pyrimidinones / Q000627:therapeutic use*
D047428:Protein Kinase Inhibitors; D011728:Pyridones; D011744:Pyrimidinones; C558666:TAK 733; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D020930:MAP Kinase Kinase Kinases