Cited by 481Melanoma and MAPK PathwaysLung Cancer Treatments and MutationsProtein Tyrosine Phosphatases

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MAP Kinase Pathway Alterations in BRAF -Mutant Melanoma Patients with Acquired Resistance to Combined RAF/MEK Inhibition

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Wagle, Nikhil, Van Allen, Eliezer M., Treacy, Daniel J., Frederick, Dennie T., Cooper, Zachary A., Taylor-Weiner, Amaro, Rosenberg, Mara, Goetz, Eva M., Sullivan, Ryan J., Farlow, Deborah N., Friedrich, Dennis C., Anderka, Kristin, Perrin, Danielle, Johannessen, Cory M., McKenna, Aaron, Cibulskis, Kristian, Kryukov, Gregory, Hodis, Eran, Lawrence, Donald P., Fisher, Sheila, Getz, Gad, Gabriel, Stacey B., Carter, Scott L., Flaherty, Keith T., Wargo, Jennifer A., Garraway, Levi A.·2014·Cancer Discovery

DOI 10.1158/2159-8290.cd-13-0631PMC PMC3947296

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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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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: Wagle, Nikhil
Frederick, Dennie T.
Cooper, Zachary A.
Taylor-Weiner, Amaro
Rosenberg, Mara
Sullivan, Ryan J.
Johannessen, Cory M.
McKenna, Aaron
Cibulskis, Kristian
Kryukov, Gregory
Hodis, Eran
Lawrence, Donald P.
Getz, Gad
Gabriel, Stacey B.
Carter, Scott L.
Flaherty, Keith T.
Wargo, Jennifer A.
Garraway, Levi A.
Venue: Cancer Discovery
Publisher: American Association for Cancer Research (AACR)
Published: 2014-01-01
Volume: 4
Issue: 1
Pages: 61-68
ISSN: 2159-8274 (ISSN-L)
2159-8290
DOI: 10.1158/2159-8290.cd-13-0631
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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MAP Kinase Pathway Alterations in BRAF -Mutant Melanoma Patients with Acquired Resistance to Combined RAF/MEK Inhibition

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