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

Author

Listed:
  • Jennifer O. Lauchle

    (Department of Pediatrics,)

  • Doris Kim

    (Department of Pediatrics,)

  • Doan T. Le

    (Department of Pediatrics,)

  • Keiko Akagi

    (Mouse Cancer Genetics Program, National Cancer Institute, Fredrick, Maryland 21702, USA)

  • Michael Crone

    (Department of Pediatrics,)

  • Kimberly Krisman

    (Department of Pediatrics,)

  • Kegan Warner

    (Department of Pediatrics,)

  • Jeannette M. Bonifas

    (Department of Pediatrics,)

  • Qing Li

    (Department of Medicine,)

  • Kristen M. Coakley

    (Department of Anatomy,)

  • Ernesto Diaz-Flores

    (Department of Pediatrics,)

  • Matthew Gorman

    (Department of Pediatrics,)

  • Sally Przybranowski

    (Pfizer Global Research and Development, Ann Arbor, Michigan 48105, USA)

  • Mary Tran

    (Department of Pediatrics,)

  • Scott C. Kogan

    (University of California, San Francisco, California 94143, USA)

  • Jeroen P. Roose

    (Department of Anatomy,)

  • Neal G. Copeland

    (Institute of Molecular and Cell Biology)

  • Nancy A. Jenkins

    (Institute of Molecular and Cell Biology)

  • Luis Parada

    (University of Texas Southwestern, Dallas, Texas 75235, USA)

  • Linda Wolff

    (Laboratory of Cellular Oncology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA)

  • Judith Sebolt-Leopold

    (Pfizer Global Research and Development, Ann Arbor, Michigan 48105, USA)

  • Kevin Shannon

    (Department of Pediatrics,)

Abstract

MEK inhibitor resistance linked to Ras In a mouse model for myeloproliferative disorder (MPD) driven by loss of NF-1 (which activates the Ras–MEK–MAPK pathway), additional mutations were created by insertional mutagenesis that led to progression of the disease to acute myeloid leukaemias (AMLs). Interestingly, MEK inhibitors are not effective in mice with MPD, but lead to tumour regression in AMLs. However, these mice eventually develop resistance to MEK inhibitors. This was linked to insertional mutagenesis at genes encoding RasGRP1 and p38 in subclones of the AMLs that are present prior to and selected for during treatment with MEK inhibitors.

Suggested Citation

  • Jennifer O. Lauchle & Doris Kim & Doan T. Le & Keiko Akagi & Michael Crone & Kimberly Krisman & Kegan Warner & Jeannette M. Bonifas & Qing Li & Kristen M. Coakley & Ernesto Diaz-Flores & Matthew Gorma, 2009. "Response and resistance to MEK inhibition in leukaemias initiated by hyperactive Ras," Nature, Nature, vol. 461(7262), pages 411-414, September.
    • Handle: RePEc:nat:nature:v:461:y:2009:i:7262:d:10.1038_nature08279
    DOI: 10.1038/nature08279
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    Cited by:

    1. Cong Wang & Xue Li & Binbin Xue & Changping Yu & Luoling Wang & Rilin Deng & Hui Liu & Zihao Chen & Yingdan Zhang & Suping Fan & Chaohui Zuo & Hungyu Sun & Haizhen Zhu & Jianli Wang & Songqing Tang, 2022. "RasGRP1 promotes the acute inflammatory response and restricts inflammation-associated cancer cell growth," Nature Communications, Nature, vol. 13(1), pages 1-17, December.

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