ACS Medicinal Chemistry Letters
Letter
Chapman, P. B. Inhibition of mutated, activated BRAF in metastatic
melanoma. N. Engl. J. Med. 2010, 363, 809−19.
explosive and is usually identified only during radiographic
imaging of tumor masses, making it difficult to implement an
appropriate salvage therapy within time.41
(7) Chapman, P. B.; Hauschild, A.; Robert, C.; Haanen, J. B.; Ascierto,
P.; Larkin, J.; Dummer, R.; Garbe, C.; Testori, A.; Maio, M.; Hogg, D.;
Lorigan, P.; Lebbe, C.; Jouary, T.; Schadendorf, D.; Ribas, A.; O’Day, S.
J.; Sosman, J. A.; Kirkwood, J. M.; Eggermont, A. M.; Dreno, B.; Nolop,
K.; Li, J.; Nelson, B.; Hou, J.; Lee, R. J.; Flaherty, K. T.; McArthur, G. A.
Improved survival with vemurafenib in melanoma with BRAF V600E
mutation. N. Engl. J. Med. 2011, 364, 2507−16.
The experiments reported here provide support for the notion
that a peptide-based sensor may be used to quantify ERK activity
in patient tissue samples. Currently, available methods such as
immunohistochemistry performed on archival tissue can be
notoriously unreliable and nonquantitative, with extreme
sensitivity to fixation methods and processing variation across
sites.42 Studies are currently ongoing to evaluate the ability of the
sensor to quantify ERK activity in primary melanoma tumors.
(8) Sosman, J. A.; Kim, K. B.; Schuchter, L.; Gonzalez, R.; Pavlick, A.
C.; Weber, J. S.; McArthur, G. A.; Hutson, T. E.; Moschos, S. J.; Flaherty,
K. T.; Hersey, P.; Kefford, R.; Lawrence, D.; Puzanov, I.; Lewis, K. D.;
Amaravadi, R. K.; Chmielowski, B.; Lawrence, H. J.; Shyr, Y.; Ye, F.; Li,
J.; Nolop, K. B.; Lee, R. J.; Joe, A. K.; Ribas, A. Survival in BRAF V600-
mutant advanced melanoma treated with vemurafenib. N. Engl. J. Med.
2012, 366, 707−14.
(9) Flaherty, K. T.; Infante, J. R.; Daud, A.; Gonzalez, R.; Kefford, R. F.;
Sosman, J.; Hamid, O.; Schuchter, L.; Cebon, J.; Ibrahim, N.;
Kudchadkar, R.; Burris, H. A.; Falchook, G.; Algazi, A.; Lewis, K.;
Long, G. V.; Puzanov, I.; Lebowitz, P.; Singh, A.; Little, S.; Sun, P.;
Allred, A.; Ouellet, D.; Kim, K. B.; Patel, K.; Weber, J. Combined BRAF
and MEK inhibition in melanoma with BRAF V600 Mutations. N. Engl.
J. Med. 2012, 367, 1694−703.
ASSOCIATED CONTENT
* Supporting Information
Reagents and detailed experimental procedures. This material is
■
S
AUTHOR INFORMATION
Corresponding Authors
■
(10) Hauschild, A.; Grob, J. J.; Demidov, L. V.; Jouary, T.; Gutzmer, R.;
Millward, M.; Rutkowski, P.; Blank, C. U.; Miller, W. H., Jr.; Kaempgen,
E.; Martin-Algarra, S.; Karaszewska, B.; Mauch, C.; Chiarion-Sileni, V.;
Martin, A. M.; Swann, S.; Haney, P.; Mirakhur, B.; Guckert, M. E.;
Goodman, V.; Chapman, P. B. Dabrafenib in BRAF-mutated metastatic
melanoma: a multicentre, open-label, phase 3 randomised controlled
trial. Lancet 2012, 380, 358−65.
(11) Long, G. V.; Trefzer, U.; Davies, M. A.; Kefford, R. F.; Ascierto, P.
A.; Chapman, P. B.; Puzanov, I.; Hauschild, A.; Robert, C.; Algazi, A.;
Mortier, L.; Tawbi, H.; Wilhelm, T.; Zimmer, L.; Switzky, J.; Swann, S.;
Martin, A. M.; Guckert, M.; Goodman, V.; Streit, M.; Kirkwood, J. M.;
Schadendorf, D. Dabrafenib in patients with Val600Glu or Val600Lys
BRAF-mutant melanoma metastatic to the brain (BREAK-MB): a
multicentre, open-label, phase 2 trial. Lancet Oncol. 2012, 13, 1087−95.
(12) Bollag, G.; Hirth, P.; Tsai, J.; Zhang, J.; Ibrahim, P. N.; Cho, H.;
Spevak, W.; Zhang, C.; Zhang, Y.; Habets, G.; Burton, E. A.; Wong, B.;
Tsang, G.; West, B. L.; Powell, B.; Shellooe, R.; Marimuthu, A.; Nguyen,
H.; Zhang, K. Y.; Artis, D. R.; Schlessinger, J.; Su, F.; Higgins, B.; Iyer, R.;
D’Andrea, K.; Koehler, A.; Stumm, M.; Lin, P. S.; Lee, R. J.; Grippo, J.;
Puzanov, I.; Kim, K. B.; Ribas, A.; McArthur, G. A.; Sosman, J. A.;
Chapman, P. B.; Flaherty, K. T.; Xu, X.; Nathanson, K. L.; Nolop, K.
Clinical efficacy of a RAF inhibitor needs broad target blockade in
BRAF-mutant melanoma. Nature 2010, 467, 596−9.
Author Contributions
⊥These authors contributed equally to this work.
Funding
Support by NIH (GM059802, GM106137, and CA167505), the
Welch Foundation (F-1390 and F-1691), CPRIT (RP101501,
RP140648, and RP140649), a Cyrus Scholar Award, and the
DXB Biosciences Research Fund is acknowledged.
Notes
The authors declare no competing financial interest.
ABBREVIATIONS
■
Sox, 8-hydroxy-5-(N,N-dimethylsulfonamido)-2-methylquino-
line; Ets, murine (His6-tagged)Ets1(1−138); ERK-sensor-D1,
FQRKTLQRRLKGLNLNL-XXX-TGPLSPC(SOX)PF
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dx.doi.org/10.1021/ml500198b | ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX