The DOI matches its Crossref record; 42 of the 42 references it cites were found in a registry or an index.
RAS Mutations Are Associated With the Development of Cutaneous Squamous Cell Tumors in Patients Treated With RAF Inhibitors
Open accessAbstract
Purpose: RAF inhibitors are effective against melanomas with BRAF V600E mutations but may induce keratoacanthomas (KAs) and cutaneous squamous cell carcinomas (cSCCs). The potential of these agents to promote secondary malignancies is concerning. We analyzed cSCC and KA lesions for genetic mutations in an attempt to identify an underlying mechanism for their formation. Methods: Four international centers contributed 237 KA or cSCC tumor samples from patients receiving an RAF inhibitor (either vemurafenib or sorafenib; n = 19) or immunosuppression therapy (n = 53) or tumors that developed spontaneously (n = 165). Each sample was profiled for 396 known somatic mutations across 33 cancer-related genes by using a mass spectrometric–based genotyping platform. Results: Mutations were detected in 16% of tumors (38 of 237), with five tumors harboring two mutations. Mutations in TP53, CDKN2A, HRAS, KRAS, and PIK3CA were previously described in squamous cell tumors. Mutations in MYC, FGFR3, and VHL were identified for the first time. A higher frequency of activating RAS mutations was found in tumors from patients treated with an RAF inhibitor versus populations treated with a non–RAF inhibitor (21.1% v 3.2%; P < .01), although overall mutation rates between treatment groups were similar (RAF inhibitor, 21.1%; immunosuppression, 18.9%; and spontaneous, 17.6%; P = not significant). Tumor histology (KA v cSCC), tumor site (head and neck v other), patient age (≤ 70 v > 70 years), and sex had no significant impact on mutation rate or type. Conclusion: Squamous cell tumors from patients treated with an RAF inhibitor have a distinct mutational profile that supports a mechanism of therapy-induced tumorigenesis in RAS-primed cells. Conceivably, cotargeting of MEK together with RAF may reduce or prevent formation of these tumors.
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Cites
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Improved survival with vemurafenib in melanoma with BRAF V600E mutation
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Self-citationGenetic Alterations during Colorectal-Tumor Development
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Inhibition of Mutated, Activated BRAF in Metastatic Melanoma
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Self-citationMelanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation
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Self-citationRAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type BRAF
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RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth
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Kinase-Dead BRAF and Oncogenic RAS Cooperate to Drive Tumor Progression through CRAF
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Self-citationCombined Vemurafenib and Cobimetinib in BRAF -Mutated Melanoma
Larkin, J., Ascierto, P. A., Dréno, B., Atkinson, V., Liszkay, G., Maio, M., Mandalà, M., Demidov, L., Stroyakovskiy, D., Thomas, L., et al. (2014) · New England Journal of Medicine · doi:10.1056/nejmoa1408868 · Cited by 2,068
Self-citationDrugging the undruggable RAS: Mission Possible?
Cox, A. D., Fesik, S. W., Kimmelman, A. C., Luo, J., & Der, C. J. (2014) · Nature Reviews Drug Discovery · doi:10.1038/nrd4389 · Cited by 1,997
Combined BRAF and MEK Inhibition versus BRAF Inhibition Alone in Melanoma
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Self-citationERK1/2 MAP kinases: Structure, function, and regulation
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Metadata
- Authors
- Oberholzer, P. A., Kee, D., Dziunycz, P., Sucker, A., Kamsukom, N., Jones, R., Roden, C., Chalk, C. J., Ardlie, K., Palescandolo, E., Piris, A., MacConaill, L. E., Robert, C., Hofbauer, G. F. L., McArthur, G. A., Schadendorf, D., & Garraway, L. A.
- Venue
- Journal of Clinical Oncology
- Published
- 2012-01-20
- Volume
- 30
- Issue
- 3
- Pages
- 316-321
- ISSN
- 0732-183X (ISSN-L)
- 1527-7755
- OpenAlex
- W2023046293
- Cited by
- 386
- References
- 42
- FWCI
- 38.25
- Type
- journal article
- Language
- en
- Open access
- bronze
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- Oberholzer, P. A., Kee, D., Dziunycz, P., Sucker, A., Kamsukom, N., Jones, R., Roden, C., Chalk, C. J., Ardlie, K., Palescandolo, E., Piris, A., MacConaill, L. E., Robert, C., Hofbauer, G. F. L., McArthur, G. A., Schadendorf, D., & Garraway, L. A. (2012). RAS Mutations Are Associated With the Development of Cutaneous Squamous Cell Tumors in Patients Treated With RAF Inhibitors. Journal of Clinical Oncology. https://doi.org/10.1200/jco.2011.36.7680
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