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COT drives resistance to RAF inhibition through MAP kinase pathway reactivation
Open accessAbstract
Oncogenic mutations in the serine/threonine kinase B-RAF (also known as BRAF) are found in 50-70% of malignant melanomas. Pre-clinical studies have demonstrated that the B-RAF(V600E) mutation predicts a dependency on the mitogen-activated protein kinase (MAPK) signalling cascade in melanoma-an observation that has been validated by the success of RAF and MEK inhibitors in clinical trials. However, clinical responses to targeted anticancer therapeutics are frequently confounded by de novo or acquired resistance. Identification of resistance mechanisms in a manner that elucidates alternative 'druggable' targets may inform effective long-term treatment strategies. Here we expressed ∼600 kinase and kinase-related open reading frames (ORFs) in parallel to interrogate resistance to a selective RAF kinase inhibitor. We identified MAP3K8 (the gene encoding COT/Tpl2) as a MAPK pathway agonist that drives resistance to RAF inhibition in B-RAF(V600E) cell lines. COT activates ERK primarily through MEK-dependent mechanisms that do not require RAF signalling. Moreover, COT expression is associated with de novo resistance in B-RAF(V600E) cultured cell lines and acquired resistance in melanoma cells and tissue obtained from relapsing patients following treatment with MEK or RAF inhibitors. We further identify combinatorial MAPK pathway inhibition or targeting of COT kinase activity as possible therapeutic strategies for reducing MAPK pathway activation in this setting. Together, these results provide new insights into resistance mechanisms involving the MAPK pathway and articulate an integrative approach through which high-throughput functional screens may inform the development of novel therapeutic strategies.
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“BRAF inhibitors have proven ineffective as single agents due to adaptive feedback re-activation of the MAPK and other signaling pathways [5–13, 38].”
From Co-targeting SRC overcomes resistance to BRAF inhibitors in colorectal cancer (2025) · cites this paper as [13]
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Metadata
- Authors
- 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., Caponigro, G., Hieronymus, H., Murray, R. R., Salehi-Ashtiani, K., Hill, D. E., Vidal, M., Zhao, J. J., Yang, X., Alkan, O., Kim, S., Harris, J. L., Wilson, C. J., Myer, V. E., Finan, P. M., Root, D. E., Roberts, T. M., Golub, T., Flaherty, K. T., Dummer, R., Weber, B. L., Sellers, W. R., Schlegel, R., Wargo, J. A., Hahn, W. C., & Garraway, L. A.
- Affiliations
- Broad Institute (US)
- Harvard University (US)
- Massachusetts General Hospital (US)
- Genomics Institute of the Novartis Research Foundation (US)
- Dana-Farber Cancer Institute (US)
- University of Zurich (CH)
- Corresponding author
- Garraway, Levi A.
- ORCID
- Johannessen, Cory M.
- Boehm, Jesse S.
- Kim, So Young
- Stransky, Nicolas
- Cogdill, Alexandria P.
- Barretina, Jordi
- Hill, David E.
- Vidal, Marc
- Zhao, Jean J.
- Yang, Xiaoping
- Alkan, Ozan
- Wilson, Christopher J.
- Myer, Vic E.
- Root, David E.
- Roberts, Thomas M.
- Golub, Todd
- Flaherty, Keith T.
- Dummer, Reinhard
- Weber, Barbara L.
- Sellers, William R.
- Wargo, Jennifer A.
- Hahn, William C.
- Garraway, Levi A.
- Venue
- Nature
- Published
- 2010-11-24
- Volume
- 468
- Issue
- 7326
- Pages
- 968-972
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3058384
- OpenAlex
- W2141674733
- Cited by
- 1,460
- References
- 30
- Citations by year
- 2026: 19 · 2025: 27 · 2024: 32 · 2023: 55 · 2022: 45 · 2021: 56 · 2020: 67 · 2019: 91 · 2018: 78 · 2017: 102 · 2016: 107 · 2015: 121 · 2014: 158 · 2013: 186 · 2012: 177
- FWCI
- 65.49
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Zurich Open Repository and Archive (University of Zurich) (submittedVersion)
- Funders
- National Institutes of Health (DP2OD002750)
- National Cancer Institute (RC2CA148268, R01CA134502, K08CA115927, CA134502, R33CA128625, P50CA093683)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Keywords
- MAP3K8, BRAF inhibitor resistance, vemurafenib, melanoma, BRAF V600E mutation, MAPK signaling
- MeSH terms
- Vemurafenib, Allosteric Regulation, Clinical Trials as Topic, Enzyme Activation, Humans, Indoles, Melanoma, Proto-Oncogene Proteins, Sulfonamides, Gene Library, Gene Expression Regulation, Neoplastic, Open Reading Frames, Drug Resistance, Neoplasm, Proto-Oncogene Proteins c-raf, Gene Expression Profiling, Mitogen-Activated Protein Kinases, Mitogen-Activated Protein Kinase Kinases, MAP Kinase Kinase Kinases, MAP Kinase Signaling System, Cell Line, Tumor, Protein Kinase Inhibitors, Proto-Oncogene Proteins B-raf
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