Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.


Sci. Signal., 23 November 2010
Vol. 3, Issue 149, p. ra84
[DOI: 10.1126/scisignal.2001148]


BRAF Gene Amplification Can Promote Acquired Resistance to MEK Inhibitors in Cancer Cells Harboring the BRAF V600E Mutation

Ryan B. Corcoran1,2, Dora Dias-Santagata3, Kristin Bergethon3, A. John Iafrate3, Jeffrey Settleman1,2*, and Jeffrey A. Engelman1,2*

1 Massachusetts General Hospital Cancer Center, Boston, MA 02129, USA.
2 Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
3 Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02115, USA.

Abstract: Oncogenic BRAF mutations are found in several tumor types, including melanomas and colorectal cancers. Tumors with BRAF mutations have increased mitogen-activated protein kinase pathway activity and heightened sensitivity to BRAF and MEK (mitogen-activated or extracellular signal–regulated protein kinase kinase) inhibitors. To identify potential mechanisms of acquired drug resistance, we generated clones resistant to the allosteric MEK inhibitor AZD6244 from two BRAF V600E mutant colorectal cancer cell lines that are highly sensitive to MEK or BRAF inhibition. These AZD6244-resistant (AR) clones, which exhibited cross-resistance to BRAF inhibitors, acquired resistance through amplification of the BRAF gene. A small percentage of treatment-naïve parental cells showed preexisting BRAF amplification. We observed similar amplification in a subset of cells in a BRAF-mutant colorectal cancer. In cell lines, BRAF amplification increased the abundance of phosphorylated MEK and impaired the ability of AZD6244 to inhibit ERK (extracellular signal–regulated kinase) phosphorylation. The ability of AZD6244 to inhibit ERK phosphorylation in AR cells was restored by treatment with a BRAF inhibitor at low concentrations that reduced the abundance of phosphorylated MEK to amounts observed in parental cells. Combined MEK and BRAF inhibition fully overcame resistance to MEK or BRAF inhibitors alone and was also more effective in parental cells compared to treatment with either inhibitor alone. These findings implicate BRAF amplification as a mechanism of resistance to both MEK and BRAF inhibitors and suggest combined MEK and BRAF inhibition as a clinical strategy to overcome, or possibly prevent, this mechanism of resistance.

* To whom correspondence should be addressed. E-mail: Settleman.jeffrey{at} (J.S.); jengelman{at} (J.A.E.)

Citation: R. B. Corcoran, D. Dias-Santagata, K. Bergethon, A. J. Iafrate, J. Settleman, J. A. Engelman, BRAF Gene Amplification Can Promote Acquired Resistance to MEK Inhibitors in Cancer Cells Harboring the BRAF V600E Mutation. Sci. Signal. 3, ra84 (2010).

Read the Full Text

Loss of NF1 in Cutaneous Melanoma Is Associated with RAS Activation and MEK Dependence.
M. H. Nissan, C. A. Pratilas, A. M. Jones, R. Ramirez, H. Won, C. Liu, S. Tiwari, L. Kong, A. J. Hanrahan, Z. Yao, et al. (2014)
Cancer Res. 74, 2340-2350
   Abstract »    Full Text »    PDF »
BRAF Inhibitor Resistance Mechanisms in Metastatic Melanoma: Spectrum and Clinical Impact.
H. Rizos, A. M. Menzies, G. M. Pupo, M. S. Carlino, C. Fung, J. Hyman, L. E. Haydu, B. Mijatov, T. M. Becker, S. C. Boyd, et al. (2014)
Clin. Cancer Res. 20, 1965-1977
   Abstract »    Full Text »    PDF »
Overcoming Acquired BRAF Inhibitor Resistance in Melanoma via Targeted Inhibition of Hsp90 with Ganetespib.
J. Acquaviva, D. L. Smith, J.-P. Jimenez, C. Zhang, M. Sequeira, S. He, J. Sang, R. C. Bates, and D. A. Proia (2014)
Mol. Cancer Ther. 13, 353-363
   Abstract »    Full Text »    PDF »
Towards a Unified Model of RAF Inhibitor Resistance.
D. B. Solit and N. Rosen (2014)
Cancer Discovery 4, 27-30
   Abstract »    Full Text »    PDF »
MAP Kinase Pathway Alterations in BRAF-Mutant Melanoma Patients with Acquired Resistance to Combined RAF/MEK Inhibition.
N. Wagle, E. M. Van Allen, D. J. Treacy, D. T. Frederick, Z. A. Cooper, A. Taylor-Weiner, M. Rosenberg, E. M. Goetz, R. J. Sullivan, D. N. Farlow, et al. (2014)
Cancer Discovery 4, 61-68
   Abstract »    Full Text »    PDF »
Development, Characterization, and Reversal of Acquired Resistance to the MEK1 Inhibitor Selumetinib (AZD6244) in an In Vivo Model of Childhood Astrocytoma.
H. K. Bid, A. Kibler, D. A. Phelps, S. Manap, L. Xiao, J. Lin, D. Capper, D. Oswald, B. Geier, M. DeWire, et al. (2013)
Clin. Cancer Res. 19, 6716-6729
   Abstract »    Full Text »    PDF »
Antitumor Activity of the Selective Pan-RAF Inhibitor TAK-632 in BRAF Inhibitor-Resistant Melanoma.
A. Nakamura, T. Arita, S. Tsuchiya, J. Donelan, J. Chouitar, E. Carideo, K. Galvin, M. Okaniwa, T. Ishikawa, and S. Yoshida (2013)
Cancer Res. 73, 7043-7055
   Abstract »    Full Text »    PDF »
Tumor Genetic Analyses of Patients with Metastatic Melanoma Treated with the BRAF Inhibitor Dabrafenib (GSK2118436).
K. L. Nathanson, A.-M. Martin, B. Wubbenhorst, J. Greshock, R. Letrero, K. D'Andrea, S. O'Day, J. R. Infante, G. S. Falchook, H.-T. Arkenau, et al. (2013)
Clin. Cancer Res. 19, 4868-4878
   Abstract »    Full Text »    PDF »
Rational Combination of a MEK Inhibitor, Selumetinib, and the Wnt/Calcium Pathway Modulator, Cyclosporin A, in Preclinical Models of Colorectal Cancer.
A. Spreafico, J. J. Tentler, T. M. Pitts, A. C. Tan, M. A. Gregory, J. J. Arcaroli, P. J. Klauck, M. C. McManus, R. J. Hansen, J. Kim, et al. (2013)
Clin. Cancer Res. 19, 4149-4162
   Abstract »    Full Text »    PDF »
TORC1 Suppression Predicts Responsiveness to RAF and MEK Inhibition in BRAF-Mutant Melanoma.
R. B. Corcoran, S. M. Rothenberg, A. N. Hata, A. C. Faber, A. Piris, R. M. Nazarian, R. D. Brown, J. T. Godfrey, D. Winokur, J. Walsh, et al. (2013)
Science Translational Medicine 5, 196ra98
   Abstract »    Full Text »    PDF »
Discovery of a Novel ERK Inhibitor with Activity in Models of Acquired Resistance to BRAF and MEK Inhibitors.
E. J. Morris, S. Jha, C. R. Restaino, P. Dayananth, H. Zhu, A. Cooper, D. Carr, Y. Deng, W. Jin, S. Black, et al. (2013)
Cancer Discovery 3, 742-750
   Abstract »    Full Text »    PDF »
Antiproliferative Effects of Continued Mitogen-Activated Protein Kinase Pathway Inhibition following Acquired Resistance to BRAF and/or MEK Inhibition in Melanoma.
M. S. Carlino, K. Gowrishankar, C. A. B. Saunders, G. M. Pupo, S. Snoyman, X. D. Zhang, R. Saw, T. M. Becker, R. F. Kefford, G. V. Long, et al. (2013)
Mol. Cancer Ther. 12, 1332-1342
   Abstract »    Full Text »    PDF »
Evolutionary dynamics of cancer in response to targeted combination therapy.
I. Bozic, J. G. Reiter, B. Allen, T. Antal, K. Chatterjee, P. Shah, Y. S. Moon, A. Yaqubie, N. Kelly, D. T. Le, et al. (2013)
eLife Sci 2, e00747
   Abstract »    Full Text »    PDF »
Effect of SMURF2 Targeting on Susceptibility to MEK Inhibitors in Melanoma.
M. P. Smith, J. Ferguson, I. Arozarena, R. Hayward, R. Marais, A. Chapman, A. Hurlstone, and C. Wellbrock (2013)
J Natl Cancer Inst 105, 33-46
   Abstract »    Full Text »    PDF »
The crossregulation between ERK and PI3K signaling pathways determines the tumoricidal efficacy of MEK inhibitor.
J.-K. Won, H. W. Yang, S.-Y. Shin, J. H. Lee, W. D. Heo, and K.-H. Cho (2012)
J Mol Cell Biol 4, 153-163
   Abstract »    Full Text »    PDF »
Bridging the Gap between Preclinical and Clinical Studies Using Pharmacokinetic-Pharmacodynamic Modeling: An Analysis of GDC-0973, a MEK Inhibitor.
H. Wong, L. Vernillet, A. Peterson, J. A. Ware, L. Lee, J.-F. Martini, P. Yu, C. Li, G. D. Rosario, E. F. Choo, et al. (2012)
Clin. Cancer Res. 18, 3090-3099
   Abstract »    Full Text »    PDF »
Distinct requirement for an intact dimer interface in wild-type, V600E and kinase-dead B-Raf signalling.
M. Roring, R. Herr, G. J. Fiala, K. Heilmann, S. Braun, A. E. Eisenhardt, S. Halbach, D. Capper, A. von Deimling, W. W. Schamel, et al. (2012)
EMBO J. 31, 2629-2647
   Abstract »    Full Text »    PDF »
Cooperative interactions of BRAFV600E kinase and CDKN2A locus deficiency in pediatric malignant astrocytoma as a basis for rational therapy.
E. Huillard, R. Hashizume, J. J. Phillips, A. Griveau, R. A. Ihrie, Y. Aoki, T. Nicolaides, A. Perry, T. Waldman, M. McMahon, et al. (2012)
PNAS 109, 8710-8715
   Abstract »    Full Text »    PDF »
Complexity in the signaling network: insights from the use of targeted inhibitors in cancer therapy.
J. S. Logue and D. K. Morrison (2012)
Genes & Dev. 26, 641-650
   Abstract »    Full Text »    PDF »
Circumventing Cancer Drug Resistance in the Era of Personalized Medicine.
L. A. Garraway and P. A. Janne (2012)
Cancer Discovery 2, 214-226
   Abstract »    Full Text »    PDF »
EGFR-Mediated Reactivation of MAPK Signaling Contributes to Insensitivity of BRAF-Mutant Colorectal Cancers to RAF Inhibition with Vemurafenib.
R. B. Corcoran, H. Ebi, A. B. Turke, E. M. Coffee, M. Nishino, A. P. Cogdill, R. D. Brown, P. Della Pelle, D. Dias-Santagata, K. E. Hung, et al. (2012)
Cancer Discovery 2, 227-235
   Abstract »    Full Text »    PDF »
Mechanisms of Acquired Crizotinib Resistance in ALK-Rearranged Lung Cancers.
R. Katayama, A. T. Shaw, T. M. Khan, M. Mino-Kenudson, B. J. Solomon, B. Halmos, N. A. Jessop, J. C. Wain, A. T. Yeo, C. Benes, et al. (2012)
Science Translational Medicine 4, 120ra17
   Abstract »    Full Text »    PDF »
Dissecting Therapeutic Resistance to RAF Inhibition in Melanoma by Tumor Genomic Profiling.
N. Wagle, C. Emery, M. F. Berger, M. J. Davis, A. Sawyer, P. Pochanard, S. M. Kehoe, C. M. Johannessen, L. E. MacConaill, W. C. Hahn, et al. (2011)
J. Clin. Oncol. 29, 3085-3096
   Abstract »    Full Text »    PDF »
Therapeutic strategies to overcome crizotinib resistance in non-small cell lung cancers harboring the fusion oncogene EML4-ALK.
R. Katayama, T. M. Khan, C. Benes, E. Lifshits, H. Ebi, V. M. Rivera, W. C. Shakespeare, A. J. Iafrate, J. A. Engelman, and A. T. Shaw (2011)
PNAS 108, 7535-7540
   Abstract »    Full Text »    PDF »
Amplification of the Driving Oncogene, KRAS or BRAF, Underpins Acquired Resistance to MEK1/2 Inhibitors in Colorectal Cancer Cells.
A. S. Little, K. Balmanno, M. J. Sale, S. Newman, J. R. Dry, M. Hampson, P. A. W. Edwards, P. D. Smith, and S. J. Cook (2011)
Science Signaling 4, ra17
   Abstract »    Full Text »    PDF »
Resistance to MEK Inhibitors: Should We Co-Target Upstream?.
P. I. Poulikakos and D. B. Solit (2011)
Science Signaling 4, pe16
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882