The DOI matches its Crossref record; 34 of the 34 references it cites were found in a registry or an index.
Acquired BRAF inhibitor resistance: A multicenter meta-analysis of the spectrum and frequencies, clinical behaviour, and phenotypic associations of resistance mechanisms
Open accessAbstract
Background Acquired resistance to BRAF inhibitors (BRAFi) is a near-universal phenomenon caused by numerous genetic and non-genetic alterations. In this study, we evaluated the spectrum, onset, pattern of progression, and subsequent clinical outcomes associated with specific mechanisms of resistance. Methods We compiled clinical and genetic data from 100 patients with 132 tissue samples obtained at progression on BRAFi therapy from 3 large, previously published studies of BRAFi resistance. These samples were subjected to whole exome sequencing and/or PCR-based genetic testing. Results Among 132 samples, putative resistance mechanisms were identified in 58%, including NRAS or KRAS mutations (20%), BRAF splice variants (16%), BRAFV600E/K amplifications (13%), MEK1/2 mutations (7%), and non-MAPK pathway alterations (11%). Marked heterogeneity was observed within tumors and patients; 18 of 19 patients (95%) with >1 progression biopsy had distinct/unknown drivers of resistance between samples. NRAS mutations were associated with vemurafenib use (p=0.045) and intracranial metastases (p=0.036), and MEK1/2 mutations correlated with hepatic progression (p=0.011). Progression-free survival and overall survival were similar across resistance mechanisms. The median survival after disease progression was 6.9 months, and responses to subsequent BRAF and MEK inhibition were uncommon (2 of 15; 13%). Post-progression outcomes did not correlate with specific acquired BRAFi resistance mechanisms. Conclusions This is the first study to systematically characterize the clinical implications of particular acquired BRAFi resistance mechanisms in patients with BRAF-mutant melanoma largest study to compile the landscape of resistance. Despite marked heterogeneity of resistance mechanisms within patients, NRAS mutations correlated with vemurafenib use and intracranial disease involvement.
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Self-citationImproved survival with vemurafenib in melanoma with BRAF V600E mutation
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Self-citationMechanism of Activation of the RAF-ERK Signaling Pathway by Oncogenic Mutations of B-RAF
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Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation
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Self-citationCombined Vemurafenib and Cobimetinib in BRAF -Mutated Melanoma
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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
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Metadata
- Authors
- Johnson, D. B., Menzies, A. M., Zimmer, L., Eroglu, Z., Ye, F., Zhao, S., Rizos, H., Sucker, A., Scolyer, R. A., Gutzmer, R., Gogas, H., Kefford, R. F., Thompson, J. F., Becker, J. C., Berking, C., Egberts, F., Loquai, C., Goldinger, S. M., Pupo, G. M., Hugo, W., Kong, X., Garraway, L. A., Sosman, J. A., Ribas, A., Lo, R. S., Long, G. V., & Schadendorf, D.
- Venue
- European Journal of Cancer
- Publisher
- Elsevier BV
- Published
- 2015-12
- Volume
- 51
- Issue
- 18
- Pages
- 2792-2799
- ISSN
- 0959-8049 (ISSN-L)
- OpenAlex
- W2176310149
- Cited by
- 323
- References
- 34
- FWCI
- 2.31
- Type
- journal article
- Language
- en
- Open access
- green
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- The paper
- Johnson, D. B., Menzies, A. M., Zimmer, L., Eroglu, Z., Ye, F., Zhao, S., Rizos, H., Sucker, A., Scolyer, R. A., Gutzmer, R., Gogas, H., Kefford, R. F., Thompson, J. F., Becker, J. C., Berking, C., Egberts, F., Loquai, C., Goldinger, S. M., Pupo, G. M., . . . Schadendorf, D. (2015). Acquired BRAF inhibitor resistance: A multicenter meta-analysis of the spectrum and frequencies, clinical behaviour, and phenotypic associations of resistance mechanisms. European Journal of Cancer. https://doi.org/10.1016/j.ejca.2015.08.022
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