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A melanocyte lineage program confers resistance to MAP kinase pathway inhibition
Open accessAbstract
Malignant melanomas harbouring point mutations (Val600Glu) in the serine/threonine-protein kinase BRAF (BRAF(V600E)) depend on RAF-MEK-ERK signalling for tumour cell growth. RAF and MEK inhibitors show remarkable clinical efficacy in BRAF(V600E) melanoma; however, resistance to these agents remains a formidable challenge. Global characterization of resistance mechanisms may inform the development of more effective therapeutic combinations. Here we carried out systematic gain-of-function resistance studies by expressing more than 15,500 genes individually in a BRAF(V600E) melanoma cell line treated with RAF, MEK, ERK or combined RAF-MEK inhibitors. These studies revealed a cyclic-AMP-dependent melanocytic signalling network not previously associated with drug resistance, including G-protein-coupled receptors, adenyl cyclase, protein kinase A and cAMP response element binding protein (CREB). Preliminary analysis of biopsies from BRAF(V600E) melanoma patients revealed that phosphorylated (active) CREB was suppressed by RAF-MEK inhibition but restored in relapsing tumours. Expression of transcription factors activated downstream of MAP kinase and cAMP pathways also conferred resistance, including c-FOS, NR4A1, NR4A2 and MITF. Combined treatment with MAPK-pathway and histone-deacetylase inhibitors suppressed MITF expression and cAMP-mediated resistance. Collectively, these data suggest that oncogenic dysregulation of a melanocyte lineage dependency can cause resistance to RAF-MEK-ERK inhibition, which may be overcome by combining signalling- and chromatin-directed therapeutics.
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“Notably, sgRNAs targeting ETS2 were significantly depleted, consistent with a previous finding of its emergence as a resistance hit through a gain-of-function screen for resistance to MAPK pathway inhibitors in BRAF V600E melanoma.49”
From Paneth-like transition drives resistance to dual targeting of KRAS and EGFR in colorectal cancer (2026) · cites this paper as [49]
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“Consistent with this, analysis of primary CRC samples from previously published cohorts49 revealed strong positive correlations between SMAD1 expression, FGFR1 and FGFR3 signaling activity, and Paneth cell signatures (Figures S6A and S6B).”
From Paneth-like transition drives resistance to dual targeting of KRAS and EGFR in colorectal cancer (2026) · cites this paper as [49]
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“In melanoma, core regulators of neural crest lineage, MITF and SOX10, regulate the emergence of distinct cell states associated with drug tolerance establishment after treatment [61,82,83,84].”
From Emerging Insights into Targeted Therapy-Tolerant Persister Cells in Cancer (2021) · cites this paper as [82]
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Improved survival with vemurafenib in melanoma with BRAF V600E mutation
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Self-citationCombined BRAF and MEK inhibition in melanoma with BRAF V600 mutations
Flaherty, K. T., Infante, J. R., Daud, A., Gonzalez, R., Kefford, R. F., Sosman, J., Hamid, O., Schuchter, L., Cebon, J., Ibrahim, N., et al. (2012) · New England Journal of Medicine · doi:10.1056/nejmoa1210093 · Cited by 2,810
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Improved Survival with MEK Inhibition in BRAF-Mutated Melanoma
Flaherty, K. T., Robert, C., Hersey, P., Nathan, P., Garbe, C., Milhem, M. M., Демидов, Л. В., Hassel, J. C., Rutkowski, P. L., Mohr, P., et al. (2012) · New England Journal of Medicine · doi:10.1056/nejmoa1203421 · Cited by 2,205
Self-citationGarraway, L. A., Widlund, H. R., Rubin, M. A., Getz, G., Berger, A. J., Ramaswamy, S., Beroukhim, R., Milner, D. A., Granter, S. R., Du, J., et al. (2005) · Nature · doi:10.1038/nature03664 · Cited by 1,548
Self-citationCOT drives resistance to RAF inhibition through MAP kinase pathway reactivation
Johannessen, C. M., Boehm, J. S., Kim, S. Y., Thomas, S. R., Wardwell, L., Johnson, L. A., Emery, C. M., Stransky, N., Cogdill, A. P., Barretina, J., et al. (2010) · Nature · doi:10.1038/nature09627 · Cited by 1,460
Self-citationImproved survival with MEK Inhibition in BRAF-mutated melanoma for the METRIC Study Group
Flaherty, K. T., Robert, C., Hersey, P., Nathan, P., Garbe, C., Milhem, M. M., Демидов, Л. В., Hassel, J. C., Rutkowski, P. L., Mohr, P., et al. (2012) · Zurich Open Repository and Archive (University of Zurich) · doi:10.5167/uzh-63198 · Cited by 1,330
Self-citationBRAF mutation predicts sensitivity to MEK inhibition
Solit, D. B., Garraway, L. A., Pratilas, C. A., Sawai, A., Getz, G. A., Basso, A., Ye, Q., Lobo, J. M., She, Y., Osman, I., et al. (2005) · Nature · doi:10.1038/nature04304 · Cited by 1,326
Self-citationRaf-1 activates MAP kinase-kinase
Kyriakis, J. M., App, H., Zhang, X., Banerjee, P. T., Brautigan, D. L., Rapp, U. R., & Avruch, J. (1992) · Nature · doi:10.1038/358417a0 · Cited by 1,263
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Metadata
- Authors
- Johannessen, C. M., Johnson, L. A., Piccioni, F., Townes, A., Frederick, D. T., Donahue, M. K., Narayan, R., Flaherty, K. T., Wargo, J. A., Root, D. E., & Garraway, L. A.
- Affiliations
- Broad Institute (US)
- Massachusetts General Hospital (US)
- Corresponding author
- Garraway, Levi A.
- ORCID
- Venue
- Nature
- Published
- 2013-11-03
- Volume
- 504
- Issue
- 7478
- Pages
- 138-142
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC4098832
- OpenAlex
- W2159220884
- Cited by
- 452
- References
- 28
- Citations by year
- 2026: 8 · 2025: 15 · 2024: 19 · 2023: 22 · 2022: 27 · 2021: 32 · 2020: 49 · 2019: 45 · 2018: 36 · 2017: 57 · 2016: 48 · 2015: 41 · 2014: 47 · 2013: 4
- FWCI
- 20.92
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Institutes of Health (DP2OD002750)
- National Human Genome Research Institute (U54HG006093, U01HG006492)
- National Cancer Institute (P50-CA-93683, R33CA155554, P50CA093683, P01CA163222)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- BRAF V600E mutation, cAMP signaling, CREB, MITF, melanocyte lineage, RAF inhibitors, MEK inhibitors, histone deacetylase inhibitors, G protein-coupled receptors, adenylate cyclase, c-fos, drug resistance mechanisms, therapeutic target
- MeSH terms
- Cyclic AMP, Antineoplastic Agents, Humans, Melanocytes, Melanoma, Transcription Factors, Signal Transduction, Gene Expression Regulation, Neoplastic, Drug Resistance, Neoplasm, Cell Lineage, Mitogen-Activated Protein Kinases, Cell Line, Tumor, Protein Kinase Inhibitors, CREB-Binding Protein, HEK293 Cells
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