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COT drives resistance to RAF inhibition through MAP kinase pathway reactivation.

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.

Pubmed ID: 21107320


  • Johannessen CM
  • Boehm JS
  • Kim SY
  • Thomas SR
  • Wardwell L
  • Johnson LA
  • Emery CM
  • Stransky N
  • Cogdill AP
  • Barretina J
  • Caponigro G
  • Hieronymus H
  • Murray RR
  • Salehi-Ashtiani K
  • Hill DE
  • Vidal M
  • Zhao JJ
  • Yang X
  • Alkan O
  • Kim S
  • Harris JL
  • Wilson CJ
  • Myer VE
  • Finan PM
  • Root DE
  • Roberts TM
  • Golub T
  • Flaherty KT
  • Dummer R
  • Weber BL
  • Sellers WR
  • Schlegel R
  • Wargo JA
  • Hahn WC
  • Garraway LA



Publication Data

December 16, 2010

Associated Grants

  • Agency: NCI NIH HHS, Id: CA134502
  • Agency: NIH HHS, Id: DP2 OD002750
  • Agency: NIH HHS, Id: DP2 OD002750-01
  • Agency: NCI NIH HHS, Id: K08 CA115927
  • Agency: NCI NIH HHS, Id: K08 CA115927-05
  • Agency: NCI NIH HHS, Id: P50 CA093683
  • Agency: NCI NIH HHS, Id: R01 CA134502
  • Agency: NCI NIH HHS, Id: R33 CA128625
  • Agency: NCI NIH HHS, Id: RC2 CA148268

Mesh Terms

  • Allosteric Regulation
  • Cell Line, Tumor
  • Clinical Trials as Topic
  • Drug Resistance, Neoplasm
  • Enzyme Activation
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic
  • Gene Library
  • Humans
  • Indoles
  • MAP Kinase Kinase Kinases
  • MAP Kinase Signaling System
  • Melanoma
  • Mitogen-Activated Protein Kinase Kinases
  • Mitogen-Activated Protein Kinases
  • Open Reading Frames
  • Protein Kinase Inhibitors
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins B-raf
  • Proto-Oncogene Proteins c-raf
  • Sulfonamides