@article{8b91ea90b3fc4f1b83e106031c8e5de5,
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.",
author = "Johannessen, {Cory M.} and Boehm, {Jesse S.} and Kim, {So Young} and Thomas, {Sapana R.} and Leslie Wardwell and Johnson, {Laura A.} and Emery, {Caroline M.} and Nicolas Stransky and Cogdill, {Alexandria P.} and Jordi Barretina and Giordano Caponigro and Haley Hieronymus and Murray, {Ryan R.} and Kourosh Salehi-Ashtiani and Hill, {David E.} and Marc Vidal and Zhao, {Jean J.} and Xiaoping Yang and Ozan Alkan and Sungjoon Kim and Harris, {Jennifer L.} and Wilson, {Christopher J.} and Myer, {Vic E.} and Finan, {Peter M.} and Root, {David E.} and Roberts, {Thomas M.} and Todd Golub and Flaherty, {Keith T.} and Reinhard Dummer and Weber, {Barbara L.} and Sellers, {William R.} and Robert Schlegel and Wargo, {Jennifer A.} and Hahn, {William C.} and Garraway, {Levi A.}",
note = "Funding Information: Acknowledgements We thank members of the Broad Institute/Novartis Cancer Cell Line Encyclopedia (CCLE) for contributing cell line genomic data, expression data and pharmacological cell line sensitivity data; J. Thibault and A. Shipway for CCLE related tissue culture; R. Depinho, G. Dunn, S. Ethier, H. Greulich, A. Henderson, D. Kaplan, R. Levine, C. Miller, H. Piwnica-Worms, H. Suzuki, M. Vigny, D. Vollrath and the Harvard Institute of Proteomics for contributing templates for the kinase collection; J. Du and D. B. Wheeler for assistance with functional testing of kinases; D. A. Barbie for helpful discussions, S. E. Moody and H. W. Cheung for technical assistance, and J. K. Grenier and S.J. Silverfor compiling andannotating the list of kinases.Thiswork was supported by the NIH Director{\textquoteright}s New Innovator Award (L.A.G.), grants from the Novartis Institutes for Biomedical Research (L.A.G.), Melanoma Research Alliance (L.A.G.), Starr Cancer Consortium (L.A.G.)the US NationalCancer Institute (R33CA128625,RC2 CA148268) (W.C.H.), NIH (CA134502) (J.J.Z) the Swiss National Foundation (310040-103671) (R.D.), the Gottfried and Julia Bangerter Rhyner Stiftung (R.D.) the Ellison Foundation (M.V. and CCSB) and institute sponsored research funds from the DFCI Strategic Initiative (M.V. and CCSB).",
year = "2010",
month = dec,
day = "16",
doi = "10.1038/nature09627",
language = "English (US)",
volume = "468",
pages = "968--972",
journal = "Nature",
issn = "0028-0836",
publisher = "Nature Publishing Group",
number = "7326",
}