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MAP Kinase Pathway Alterations in BRAF -Mutant Melanoma Patients with Acquired Resistance to Combined RAF/MEK Inhibition
Open accessPublished version of a preprint
Abstract
Treatment of BRAF-mutant melanoma with combined dabrafenib and trametinib, which target RAF and the downstream MAP–ERK kinase (MEK)1 and MEK2 kinases, respectively, improves progression-free survival and response rates compared with dabrafenib monotherapy. Mechanisms of clinical resistance to combined RAF/MEK inhibition are unknown. We performed whole-exome sequencing (WES) and whole-transcriptome sequencing (RNA-seq) on pretreatment and drug-resistant tumors from five patients with acquired resistance to dabrafenib/trametinib. In three of these patients, we identified additional mitogen-activated protein kinase (MAPK) pathway alterations in the resistant tumor that were not detected in the pretreatment tumor, including a novel activating mutation in MEK2 (MEK2Q60P). MEK2Q60P conferred resistance to combined RAF/MEK inhibition in vitro, but remained sensitive to inhibition of the downstream kinase extracellular signal–regulated kinase (ERK). The continued MAPK signaling-based resistance identified in these patients suggests that alternative dosing of current agents, more potent RAF/MEK inhibitors, and/or inhibition of the downstream kinase ERK may be needed for durable control of BRAF-mutant melanoma. Significance: This study represents an initial clinical genomic study of acquired resistance to combined RAF/MEK inhibition in BRAF-mutant melanoma, using WES and RNA-seq. The presence of diverse resistance mechanisms suggests that serial biopsies and genomic/molecular profiling at the time of resistance may ultimately improve the care of patients with resistant BRAF-mutant melanoma by specifying tailored targeted combinations to overcome specific resistance mechanisms. Cancer Discov; 4(1); 61–8. ©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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“Nonetheless, resistance is pervasive, and observations so far let us conclude that, in most cases, progression to alternative strategies of drug elusion will inevitably occur [109, 140].”
From Primary and acquired resistance to EGFR-targeted therapies in colorectal cancer: impact on future treatment strategies (2014) · cites this paper as [140]
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Improved survival with vemurafenib in melanoma with BRAF V600E mutation
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Self-citationInhibition of Mutated, Activated BRAF in Metastatic Melanoma
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Self-citationCombined BRAF and MEK inhibition in melanoma with BRAF V600 mutations
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Self-citationMelanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation
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Improved Survival with MEK Inhibition in BRAF-Mutated Melanoma
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Self-citationTumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretion
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Self-citationCOT drives resistance to RAF inhibition through MAP kinase pathway reactivation
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Metadata
- Authors
- Wagle, N., Van Allen, E. M., Treacy, D. J., Frederick, D. T., Cooper, Z. A., Taylor-Weiner, A., Rosenberg, M., Goetz, E. M., Sullivan, R. J., Farlow, D. N., Friedrich, D. C., Anderka, K., Perrin, D., Johannessen, C. M., McKenna, A., Cibulskis, K., Kryukov, G., Hodis, E., Lawrence, D. P., Fisher, S., Getz, G., Gabriel, S. B., Carter, S. L., Flaherty, K. T., Wargo, J. A., & Garraway, L. A.
- Affiliations
- Broad Institute (US)
- Authors' Affiliations: 1Department of Medical Oncology, Dana-Farber Cancer Institute; 2Department of Medicine, Brigham and Women's Hospital; 3Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston; 4Broad Institute of Harvard and MIT; and 5Harvard–MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts
- Corresponding author
- Wargo, Jennifer A.
- Garraway, Levi A.
- ORCID
- Venue
- Cancer Discovery
- Published
- 2014-01-01
- Volume
- 4
- Issue
- 1
- Pages
- 61-68
- ISSN
- 2159-8274 (ISSN-L)
- 2159-8290
- PMC
- PMC3947296
- OpenAlex
- W2103557568
- Cited by
- 478
- References
- 27
- Citations by year
- 2026: 6 · 2025: 19 · 2024: 19 · 2023: 18 · 2022: 33 · 2021: 29 · 2020: 39 · 2019: 47 · 2018: 38 · 2017: 54 · 2016: 44 · 2015: 74 · 2014: 55
- FWCI
- 26.30
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cancer Discovery (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (DP2OD002750)
- National Human Genome Research Institute (U54HG003067)
- National Cancer Institute (P50-CA-93683, R33CA155554, P01 CA163222 01A1, P50CA093683, T32CA009172, P30CA016672, P01CA163222)
- National Institute of General Medical Sciences (T32GM007753)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Keywords
- BRAF-mutant melanoma, acquired drug resistance, dabrafenib, trametinib, MEK2, MAPK pathway alterations, ERK inhibition, targeted therapy resistance, resistance mechanisms
- MeSH terms
- Aged, Antineoplastic Agents, Humans, Imidazoles, Male, Melanoma, Middle Aged, Mutation, Oximes, Pyridones, Pyrimidinones, Skin Neoplasms, Signal Transduction, Drug Resistance, Neoplasm, Mitogen-Activated Protein Kinases, Mitogen-Activated Protein Kinase Kinases, Protein Kinase Inhibitors, raf Kinases, Proto-Oncogene Proteins B-raf
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