COT drives resistance to RAF inhibition through MAP kinase pathway reactivation Journal Article


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.
Article Title: COT drives resistance to RAF inhibition through MAP kinase pathway reactivation
Abstract: Oncogenic mutations in the serine/threonine kinase B-RAF (also known as BRAF) are found in 5070% 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 melanomaan 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. © 2010 Macmillan Publishers Limited. All rights reserved.
Keywords: signal transduction; mitogen activated protein kinase; controlled study; human tissue; protein expression; unclassified drug; human cell; proto-oncogene proteins; raf protein; clinical trials as topic; melanoma; enzyme inhibition; gene expression profiling; map kinase signaling system; cancer cell culture; enzyme activation; drug resistance, neoplasm; enzyme activity; gene library; cell line, tumor; protein serine threonine kinase; cancer resistance; protein kinase inhibitors; gene expression regulation, neoplastic; sulfonamides; melanoma cell; indoles; mitogen-activated protein kinases; b raf kinase; mitogen-activated protein kinase kinases; proto-oncogene proteins b-raf; allosteric regulation; proto-oncogene proteins c-raf; inhibition; open reading frame; map kinase kinase kinases; cot kinase; reactivation; open reading frames
Journal Title: Nature
Volume: 468
Issue: 7326
ISSN: 0028-0836
Publisher: Nature Publishing Group  
Date Published: 2010-12-16
Start Page: 968
End Page: 972
Language: English
DOI: 10.1038/nature09627
PUBMED: 21107320
PROVIDER: scopus
PMCID: PMC3058384
DOI/URL:
Notes: --- - "Cited By (since 1996): 11" - "Export Date: 20 April 2011" - "CODEN: NATUA" - "Source: Scopus"
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