The DOI matches its Crossref record; 8 of the 8 references it cites were found in a registry or an index.
Concurrent MEK2 Mutation and BRAF Amplification Confer Resistance to BRAF and MEK Inhibitors in Melanoma
Open accessAbstract
Although BRAF and MEK inhibitors have proven clinical benefits in melanoma, most patients develop resistance. We report a de novo MEK2-Q60P mutation and BRAF gain in a melanoma from a patient who progressed on the MEK inhibitor trametinib and did not respond to the BRAF inhibitor dabrafenib. We also identified the same MEK2-Q60P mutation along with BRAF amplification in a xenograft tumor derived from a second melanoma patient resistant to the combination of dabrafenib and trametinib. Melanoma cells chronically exposed to trametinib acquired concurrent MEK2-Q60P mutation and BRAF-V600E amplification, which conferred resistance to MEK and BRAF inhibitors. The resistant cells had sustained MAPK activation and persistent phosphorylation of S6K. A triple combination of dabrafenib, trametinib, and the PI3K/mTOR inhibitor GSK2126458 led to sustained tumor growth inhibition. Hence, concurrent genetic events that sustain MAPK signaling can underlie resistance to both BRAF and MEK inhibitors, requiring novel therapeutic strategies to overcome it.
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Cites
Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations
Flaherty, K. T., Infante, J. R., Daud, A., Gonzalez, R., Kefford, R. F., Sosman, J., Hamid, O., Schuchter, L., Cebon, J., Ibrahim, N., et al. (2012) · New England Journal of Medicine · doi:10.1056/nejmoa1210093 · Cited by 2,810
Self-citationSurvival in BRAF V600-mutant advanced melanoma treated with vemurafenib
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., et al. (2012) · New England Journal of Medicine · doi:10.1056/nejmoa1112302 · Cited by 2,156
Self-citationCOT drives resistance to RAF inhibition through MAP kinase pathway reactivation
Johannessen, C. M., Boehm, J. S., Kim, S. Y., Thomas, S. R., Wardwell, L., Johnson, L. A., Emery, C. M., Stransky, N., Cogdill, A. P., Barretina, J., et al. (2010) · Nature · doi:10.1038/nature09627 · Cited by 1,460
RAF inhibitor resistance is mediated by dimerization of aberrantly spliced BRAF(V600E)
Poulikakos, P. I., Persaud, Y., Janakiraman, M., Kong, X., Ng, C., Moriceau, G., Shi, H., Atefi, M., Titz, B., Gabay, M. T., et al. (2011) · Nature · doi:10.1038/nature10662 · Cited by 1,454
Modelling vemurafenib resistance in melanoma reveals a strategy to forestall drug resistance
Das Thakur, M., Salangsang, F., Landman, A. S., Sellers, W. R., Pryer, N. K., Levesque, M. P., Dummer, R., McMahon, M., & Stuart, D. D. (2013) · Nature · doi:10.1038/nature11814 · Cited by 730
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Self-citationInfante, J. R., Fecher, L. A., Falchook, G. S., Nallapareddy, S., Gordon, M. S., Becerra, C., DeMarini, D. J., Cox, D. S., Xu, Y., Morris, S. R., et al. (2012) · The Lancet Oncology · doi:10.1016/s1470-2045(12)70270-x · Cited by 552
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Cited by
RAS-targeted therapies: is the undruggable drugged?
Moore, A. R., Rosenberg, S. C., McCormick, F., & Malek, S. (2020) · Nature Reviews Drug Discovery · doi:10.1038/s41573-020-0068-6 · Cited by 1,103
MEK1 and MEK2 inhibitors and cancer therapy: the long and winding road
Caunt, C. J., Sale, M. J., Smith, P. D., & Cook, S. J. (2015) · Nature Reviews Cancer · doi:10.1038/nrc4000 · Cited by 606
Non-genomic and Immune Evolution of Melanoma Acquiring MAPKi Resistance
Hugo, W., Shi, H., Sun, L., Piva, M., Song, C., Kong, X., Moriceau, G., Hong, A., Dahlman, K. B., Johnson, D. B., et al. (2015) · Cell · doi:10.1016/j.cell.2015.07.061 · Cited by 600
Targeting cancer with kinase inhibitors
Gross, S., Rahal, R., Stransky, N., Lengauer, C., & Hoeflich, K. P. (2015) · Journal of Clinical Investigation · doi:10.1172/jci76094 · Cited by 444
New perspectives for targeting RAF kinase in human cancer
Karoulia, Z., Gavathiotis, E., & Poulikakos, P. I. (2017) · Nature Reviews Cancer · doi:10.1038/nrc.2017.79 · Cited by 404
Metadata
- Authors
- Villanueva, J., Infante, J. R., Krepler, C., Reyes-Uribe, P., Samanta, M., Chen, H.-Y., Li, B., Swoboda, R. K., Wilson, M., Vultur, A., Fukunaba-Kalabis, M., Wubbenhorst, B., Chen, T. Y., Liu, Q., Sproesser, K., DeMarini, D. J., Gilmer, T. M., Martin, A.-M., Marmorstein, R., Schultz, D. C., Speicher, D. W., Karakousis, G. C., Xu, W., Amaravadi, R. K., Xu, X., Schuchter, L. M., Herlyn, M., & Nathanson, K. L.
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2013-09
- Volume
- 4
- Issue
- 6
- Pages
- 1090-1099
- ISSN
- 2211-1247 (ISSN-L)
- OpenAlex
- W1982443780
- Cited by
- 187
- References
- 8
- FWCI
- 7.93
- Type
- journal article
- Language
- en
- Open access
- gold
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- CoChat. (2026). Citation check: Concurrent MEK2 Mutation and BRAF Amplification Confer Resistance to BRAF and MEK Inhibitors in Melanoma. https://app.cochat.ai/papers/10.1016/j.celrep.2013.08.023
- The paper
- Villanueva, J., Infante, J. R., Krepler, C., Reyes-Uribe, P., Samanta, M., Chen, H.-Y., Li, B., Swoboda, R. K., Wilson, M., Vultur, A., Fukunaba-Kalabis, M., Wubbenhorst, B., Chen, T. Y., Liu, Q., Sproesser, K., DeMarini, D. J., Gilmer, T. M., Martin, A.-M., Marmorstein, R., . . . Nathanson, K. L. (2013). Concurrent MEK2 Mutation and BRAF Amplification Confer Resistance to BRAF and MEK Inhibitors in Melanoma. Cell Reports. https://doi.org/10.1016/j.celrep.2013.08.023
Data sources
Bibliographic data: Semantic Scholar, OpenAlex, Crossref.
Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
Semantic Scholar’s data is described in: Kinney, R., et al. (2023). The Semantic Scholar Open Data Platform. arXiv:2301.10140.
