The DOI matches its Crossref record; 25 of the 25 references it cites were found in a registry or an index.
Dissecting Therapeutic Resistance to RAF Inhibition in Melanoma by Tumor Genomic Profiling
Open accessAbstract
A detailed understanding of the mechanisms by which tumors acquire resistance to targeted anticancer agents should speed the development of treatment strategies with lasting clinical efficacy. RAF inhibition in BRAF-mutant melanoma exemplifies the promise and challenge of many targeted drugs; although response rates are high, resistance invariably develops. Here, we articulate overarching principles of resistance to kinase inhibitors, as well as a translational approach to characterize resistance in the clinical setting through tumor mutation profiling. As a proof of principle, we performed targeted, massively parallel sequencing of 138 cancer genes in a tumor obtained from a patient with melanoma who developed resistance to PLX4032 after an initial dramatic response. The resulting profile identified an activating mutation at codon 121 in the downstream kinase MEK1 that was absent in the corresponding pretreatment tumor. The MEK1 C121S mutation was shown to increase kinase activity and confer robust resistance to both RAF and MEK inhibition in vitro. Thus, MEK1 C121S or functionally similar mutations are predicted to confer resistance to combined MEK/RAF inhibition. These results provide an instructive framework for assessing mechanisms of acquired resistance to kinase inhibition and illustrate the use of emerging technologies in a manner that may accelerate personalized cancer medicine.
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Self-citationMET Amplification Leads to Gefitinib Resistance in Lung Cancer by Activating ERBB3 Signaling
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The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP
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Tirosh, I., Izar, B., Prakadan, S. M., Wadsworth, M. H., Treacy, D., Trombetta, J. J., Rotem, A., Rodman, C., Lian, C., Murphy, G., et al. (2016) · Science · doi:10.1126/science.aad0501 · Cited by 4,944
Self-citationCancer drug resistance: an evolving paradigm
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Metadata
- Authors
- Wagle, N., Emery, C., Berger, M. F., Davis, M. J., Sawyer, A., Pochanard, P., Kehoe, S. M., Johannessen, C. M., MacConaill, L. E., Hahn, W. C., Meyerson, M., & Garraway, L. A.
- Venue
- Journal of Clinical Oncology
- Published
- 2011-08-01
- Volume
- 29
- Issue
- 22
- Pages
- 3085-3096
- ISSN
- 0732-183X (ISSN-L)
- 1527-7755
- OpenAlex
- W2017187984
- Cited by
- 1,005
- References
- 25
- FWCI
- 45.26
- Type
- journal article
- Language
- en
- Open access
- green
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- Wagle, N., Emery, C., Berger, M. F., Davis, M. J., Sawyer, A., Pochanard, P., Kehoe, S. M., Johannessen, C. M., MacConaill, L. E., Hahn, W. C., Meyerson, M., & Garraway, L. A. (2011). Dissecting Therapeutic Resistance to RAF Inhibition in Melanoma by Tumor Genomic Profiling. Journal of Clinical Oncology. https://doi.org/10.1200/jco.2010.33.2312
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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.
