MAP Kinase Pathway Alterations in BRAF -Mutant Melanoma Patients with Acquired Resistance to Combined RAF/MEK Inhibition
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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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Resistance is pervasive, and in most cases progression to alternative strategies of drug elusion will inevitably occur.
“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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- 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 · 2013: 2
- 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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