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Permanent URL to this publication: http://dx.doi.org/10.5167/uzh-41555

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 (2010). COT drives resistance to RAF inhibition through MAP kinase pathway reactivation. Nature, 468(7326):968-972.

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Abstract

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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471 citations in Web of Science®
510 citations in Scopus®
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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Dermatology Clinic
DDC:610 Medicine & health
Language:English
Date:2010
Deposited On:09 Jan 2011 17:44
Last Modified:02 Dec 2013 19:59
Publisher:Nature Publishing Group
ISSN:0028-0836
Publisher DOI:10.1038/nature09627
PubMed ID:21107320

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