The DOI matches its Crossref record; 18 of the 18 references it cites were found in a registry or an index.
The Genetic Landscape of Clinical Resistance to RAF Inhibition in Metastatic Melanoma
Open accessAbstract
Most patients with BRAFV600-mutant metastatic melanoma develop resistance to selective RAF kinase inhibitors. The spectrum of clinical genetic resistance mechanisms to RAF inhibitors and options for salvage therapy are incompletely understood. We performed whole-exome sequencing on formalin-fixed, paraffin-embedded tumors from 45 patients with BRAFV600-mutant metastatic melanoma who received vemurafenib or dabrafenib monotherapy. Genetic alterations in known or putative RAF inhibitor resistance genes were observed in 23 of 45 patients (51%). Besides previously characterized alterations, we discovered a “long tail” of new mitogen-activated protein kinase (MAPK) pathway alterations (MAP2K2, MITF) that confer RAF inhibitor resistance. In three cases, multiple resistance gene alterations were observed within the same tumor biopsy. Overall, RAF inhibitor therapy leads to diverse clinical genetic resistance mechanisms, mostly involving MAPK pathway reactivation. Novel therapeutic combinations may be needed to achieve durable clinical control of BRAFV600-mutant melanoma. Integrating clinical genomics with preclinical screens may model subsequent resistance studies. Significance: The use of RAF inhibitors for BRAFV600-mutant metastatic melanoma improves patient outcomes, but most patients demonstrate early or acquired resistance to this targeted therapy. We reveal the genetic landscape of clinical resistance mechanisms to RAF inhibitors from patients using whole-exome sequencing, and experimentally assess new observed mechanisms to define potential subsequent treatment strategies. Cancer Discov; 4(1); 94–109. ©2013 AACR. See related commentary by Solit and Rosen, p. 27 This article is highlighted in the In This Issue feature, p. 1
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Vogelstein, B., Papadopoulos, N., Velculescu, V. E., Zhou, S., Diaz, L. A., & Kinzler, K. W. (2013) · Science · doi:10.1126/science.1235122 · Cited by 7,863
Improved survival with vemurafenib in melanoma with BRAF V600E mutation
Chapman, P. B., Hauschild, A., Robert, C., Haanen, J. B., Ascierto, P., Larkin, J., Dummer, R., Garbe, C., Testori, A., Maio, M., et al. (2011) · New England Journal of Medicine · doi:10.1056/nejmoa1103782 · Cited by 7,720
Self-citationChou, T.-C., & Talalay, P. (1984) · Advances in Enzyme Regulation · doi:10.1016/0065-2571(84)90007-4 · Cited by 7,178
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
A landscape of driver mutations in melanoma
Hodis, E., Watson, I. R., Kryukov, G. V., Arold, S. T., Imielinski, M., Theurillat, J.-P., Nickerson, E., Auclair, D., Li, L., Place, C., et al. (2012) · Cell · doi:10.1016/j.cell.2012.06.024 · Cited by 2,610
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
Tumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretion
Straussman, R., Morikawa, T., Shee, K., Barzily-Rokni, M., Qian, Z. R., Du, J., Davis, A., Mongare, M. M., Gould, J., Frederick, D. T., et al. (2012) · Nature · doi:10.1038/nature11183 · Cited by 1,771
Garraway, L. A., Widlund, H. R., Rubin, M. A., Getz, G., Berger, A. J., Ramaswamy, S., Beroukhim, R., Milner, D. A., Granter, S. R., Du, J., et al. (2005) · Nature · doi:10.1038/nature03664 · Cited by 1,548
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
Self-citationRAF 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
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Self-citationA view on drug resistance in cancer
Vasan, N., Baselga, J., & Hyman, D. M. (2019) · Nature · doi:10.1038/s41586-019-1730-1 · Cited by 2,770
Llovet, J. M., Zucman-Rossi, J., Pikarsky, E., Sangro, B., Schwartz, M., Sherman, M., & Gores, G. (2016) · Nature Reviews Disease Primers · doi:10.1038/nrdp.2016.18 · Cited by 2,531
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Carreno, B. M., Magrini, V., Becker-Hapak, M., Kaabinejadian, S., Hundal, J., Petti, A. A., Ly, A., Lie, W.-R., Hildebrand, W. H., Mardis, E. R., et al. (2015) · Science · doi:10.1126/science.aaa3828 · Cited by 1,285
Metadata
- Authors
- Van Allen, E. M., Wagle, N., Sucker, A., Treacy, D. J., Johannessen, C. M., Goetz, E. M., Place, C. S., Taylor-Weiner, A., Whittaker, S., Kryukov, G. V., Hodis, E., Rosenberg, M., McKenna, A., Cibulskis, K., Farlow, D., Zimmer, L., Hillen, U., Gutzmer, R., Goldinger, S. M., Ugurel, S., Gogas, H. J., Egberts, F., Berking, C., Trefzer, U., Loquai, C., Weide, B., Hassel, J. C., Gabriel, S. B., Carter, S. L., Getz, G., Garraway, L. A., & Schadendorf, D.
- Venue
- Cancer Discovery
- Published
- 2014-01-01
- Volume
- 4
- Issue
- 1
- Pages
- 94-109
- ISSN
- 2159-8274 (ISSN-L)
- 2159-8290
- OpenAlex
- W2131040858
- Cited by
- 912
- References
- 18
- FWCI
- 35.10
- Type
- journal article
- Language
- en
- Open access
- green
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- Van Allen, E. M., Wagle, N., Sucker, A., Treacy, D. J., Johannessen, C. M., Goetz, E. M., Place, C. S., Taylor-Weiner, A., Whittaker, S., Kryukov, G. V., Hodis, E., Rosenberg, M., McKenna, A., Cibulskis, K., Farlow, D., Zimmer, L., Hillen, U., Gutzmer, R., Goldinger, S. M., . . . Schadendorf, D. (2014). The Genetic Landscape of Clinical Resistance to RAF Inhibition in Metastatic Melanoma. Cancer Discovery. https://doi.org/10.1158/2159-8290.cd-13-0617
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