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

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 Gorman, Sally Przybranowski, Mary Tran, Scott C. Kogan, Jeroen P. Roose, Neal G. Copeland, Nancy A. Jenkins, Luis Parada, Linda Wolff, Judith Sebolt-Leopold and Kevin Shannon ()
Additional contact information
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,

Nature, 2009, vol. 461, issue 7262, 411-414

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.

Date: 2009
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DOI: 10.1038/nature08279

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