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

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • 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

Published Date

  • December 2010

Published In

Volume / Issue

  • 468 / 7326

Start / End Page

  • 968 - 972

PubMed ID

  • 21107320

Pubmed Central ID

  • 21107320

Electronic International Standard Serial Number (EISSN)

  • 1476-4687

International Standard Serial Number (ISSN)

  • 0028-0836

Digital Object Identifier (DOI)

  • 10.1038/nature09627

Language

  • eng