COT drives resistance to RAF inhibition through MAP kinase pathway reactivation

Cory M. Johannessen, Jesse S. Boehm, So Young Kim, Sapana R. Thomas, Leslie Wardwell, Laura A. Johnson, Caroline M. Emery, Nicolas Stransky, Alexandria P. Cogdill, Jordi Barretina, Giordano Caponigro, Haley Hieronymus, Ryan R. Murray, Kourosh Salehi-Ashtiani, David E. Hill, Marc Vidal, Jean J. Zhao, Xiaoping Yang, Ozan Alkan, Sungjoon KimJennifer L. Harris, Christopher J. Wilson, Vic E. Myer, Peter M. Finan, David E. Root, Thomas M. Roberts, Todd Golub, Keith T. Flaherty, Reinhard Dummer, Barbara L. Weber, William R. Sellers, Robert Schlegel, Jennifer A. Wargo, William C. Hahn, Levi A. Garraway

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)968-972
Number of pages5
JournalNature
Volume468
Issue number7326
DOIs
StatePublished - Dec 16 2010

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Mitogen-Activated Protein Kinases
Phosphotransferases
Mitogen-Activated Protein Kinase Kinases
Melanoma
Therapeutics
Cell Line
Mutation
Protein-Serine-Threonine Kinases
Open Reading Frames
Cultured Cells
Observation
Clinical Trials
Genes

ASJC Scopus subject areas

  • General

Cite this

Johannessen, C. M., Boehm, J. S., Kim, S. Y., Thomas, S. R., Wardwell, L., Johnson, L. A., ... Garraway, L. A. (2010). COT drives resistance to RAF inhibition through MAP kinase pathway reactivation. Nature, 468(7326), 968-972. https://doi.org/10.1038/nature09627

COT drives resistance to RAF inhibition through MAP kinase pathway reactivation. / Johannessen, Cory M.; Boehm, Jesse S.; Kim, So Young; Thomas, Sapana R.; Wardwell, Leslie; Johnson, Laura A.; Emery, Caroline M.; Stransky, Nicolas; Cogdill, Alexandria P.; Barretina, Jordi; Caponigro, Giordano; Hieronymus, Haley; Murray, Ryan R.; Salehi-Ashtiani, Kourosh; Hill, David E.; Vidal, Marc; Zhao, Jean J.; Yang, Xiaoping; Alkan, Ozan; Kim, Sungjoon; Harris, Jennifer L.; Wilson, Christopher J.; Myer, Vic E.; Finan, Peter M.; Root, David E.; Roberts, Thomas M.; Golub, Todd; Flaherty, Keith T.; Dummer, Reinhard; Weber, Barbara L.; Sellers, William R.; Schlegel, Robert; Wargo, Jennifer A.; Hahn, William C.; Garraway, Levi A.

In: Nature, Vol. 468, No. 7326, 16.12.2010, p. 968-972.

Research output: Contribution to journalArticle

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 2010, 'COT drives resistance to RAF inhibition through MAP kinase pathway reactivation', Nature, vol. 468, no. 7326, pp. 968-972. https://doi.org/10.1038/nature09627
Johannessen CM, Boehm JS, Kim SY, Thomas SR, Wardwell L, Johnson LA et al. COT drives resistance to RAF inhibition through MAP kinase pathway reactivation. Nature. 2010 Dec 16;468(7326):968-972. https://doi.org/10.1038/nature09627
Johannessen, Cory M. ; Boehm, Jesse S. ; Kim, So Young ; Thomas, Sapana R. ; Wardwell, Leslie ; Johnson, Laura A. ; Emery, Caroline M. ; Stransky, Nicolas ; Cogdill, Alexandria P. ; Barretina, Jordi ; Caponigro, Giordano ; Hieronymus, Haley ; Murray, Ryan R. ; Salehi-Ashtiani, Kourosh ; Hill, David E. ; Vidal, Marc ; Zhao, Jean J. ; Yang, Xiaoping ; Alkan, Ozan ; Kim, Sungjoon ; Harris, Jennifer L. ; Wilson, Christopher J. ; Myer, Vic E. ; Finan, Peter M. ; Root, David E. ; Roberts, Thomas M. ; Golub, Todd ; Flaherty, Keith T. ; Dummer, Reinhard ; Weber, Barbara L. ; Sellers, William R. ; Schlegel, Robert ; Wargo, Jennifer A. ; Hahn, William C. ; Garraway, Levi A. / COT drives resistance to RAF inhibition through MAP kinase pathway reactivation. In: Nature. 2010 ; Vol. 468, No. 7326. pp. 968-972.
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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.",
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T1 - COT drives resistance to RAF inhibition through MAP kinase pathway reactivation

AU - Johannessen, Cory M.

AU - Boehm, Jesse S.

AU - Kim, So Young

AU - Thomas, Sapana R.

AU - Wardwell, Leslie

AU - Johnson, Laura A.

AU - Emery, Caroline M.

AU - Stransky, Nicolas

AU - Cogdill, Alexandria P.

AU - Barretina, Jordi

AU - Caponigro, Giordano

AU - Hieronymus, Haley

AU - Murray, Ryan R.

AU - Salehi-Ashtiani, Kourosh

AU - Hill, David E.

AU - Vidal, Marc

AU - Zhao, Jean J.

AU - Yang, Xiaoping

AU - Alkan, Ozan

AU - Kim, Sungjoon

AU - Harris, Jennifer L.

AU - Wilson, Christopher J.

AU - Myer, Vic E.

AU - Finan, Peter M.

AU - Root, David E.

AU - Roberts, Thomas M.

AU - Golub, Todd

AU - Flaherty, Keith T.

AU - Dummer, Reinhard

AU - Weber, Barbara L.

AU - Sellers, William R.

AU - Schlegel, Robert

AU - Wargo, Jennifer A.

AU - Hahn, William C.

AU - Garraway, Levi A.

PY - 2010/12/16

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