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Response and resistance to MEK inhibition in leukaemias initiated by hyperactive Ras

  1. Author:
    Lauchle, J. O.
    Kim, D.
    Le, D. T.
    Akagi, K.
    Crone, M.
    Krisman, K.
    Warner, K.
    Bonifas, J. M.
    Li, Q.
    Coakley, K. M.
    Diaz-Flores, E.
    Gorman, M.
    Przybranowski, S.
    Tran, M.
    Kogan, S. C.
    Roose, J. P.
    Copeland, N. G.
    Jenkins, N. A.

  2. Author Address

    Lauchle, Jennifer O.; Kim, Doris, Le, Doan T.; Crone, Michael, Krisman, Kimberly, Warner, Kegan, Bonifas, Jeannette M.; Diaz-Flores, Ernesto, Gorman, Matthew, Tran, Mary, Shannon, Kevin] Univ Calif San Francisco, Dept Pediat, San Francisco, CA 94143 USA. [Li, Qing] Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA. [Coakley, Kristen M.; Roose, Jeroen P.] Univ Calif San Francisco, Dept Anat, San Francisco, CA 94143 USA. [Kogan, Scott C.] Univ Calif San Francisco, Dept Lab Med, San Francisco, CA 94143 USA. [Akagi, Keiko] NCI, Mouse Canc Genet Program, Frederick, MD 21702 USA. [Przybranowski, Sally, Sebolt-Leopold, Judith] Pfizer Global Res & Dev, Ann Arbor, MI 48105 USA. [Copeland, Neal G.; Jenkins, Nancy A.] Inst Mol & Cell Biol, Singapore 138673, Singapore. [Parada, Luis] Univ Texas SW, Dallas, TX 75235 USA. [Wolff, Linda] NCI, Cellular Oncol Lab, NIH, Bethesda, MD 20892 USA.
    1. Year: 2009
  2. Journal: Nature
    1. 461
    2. 7262
    3. Pages: 411-U110
  4. Type of Article: Article
  1. Abstract:

    The cascade comprising Raf, mitogen-activated protein kinase kinase (MEK) and extracellular signal-regulated kinase (ERK) is a therapeutic target in human cancers with deregulated Ras signalling, which includes tumours that have inactivated the Nf1 tumour suppressor(1,2). Nf1 encodes neurofibromin, a GTPase-activating protein that terminates Ras signalling by stimulating hydrolysis of Ras-GTP. We compared the effects of inhibitors of MEK in a myeloproliferative disorder (MPD) initiated by inactivating Nf1 in mouse bone marrow and in acute myeloid leukaemias (AMLs) in which cooperating mutations were induced by retroviral insertional mutagenesis. Here we show that MEK inhibitors are ineffective in MPD, but induce objective regression of many Nf1-deficient AMLs. Drug resistance developed because of outgrowth of AML clones that were present before treatment. We cloned clone-specific retroviral integrations to identify candidate resistance genes including Rasgrp1, Rasgrp4 and Mapk14, which encodes p38 alpha. Functional analysis implicated increased RasGRP1 levels and reduced p38 kinase activity in resistance to MEK inhibitors. This approach represents a robust strategy for identifying genes and pathways that modulate how primary cancer cells respond to targeted therapeutics and for probing mechanisms of de novo and acquired resistance.

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  2. DOI: 10.1038/nature08279
  3. PMID: 19727076

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