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 & 2 others Judith Sebolt-Leopold, Kevin Shannon

Research output: Contribution to journalArticle

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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. Nf1 encodes neurofibromin, a GTPase-activating protein that terminates Ras signalling by stimulating hydrolysis of Rasĝ€"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 p38α. 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.

Original languageEnglish (US)
Pages (from-to)411-414
Number of pages4
JournalNature
Volume461
Issue number7262
DOIs
StatePublished - Sep 17 2009

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Mitogen-Activated Protein Kinase Kinases
Leukemia
Acute Myeloid Leukemia
Myeloproliferative Disorders
Neoplasms
Clone Cells
ras GTPase-Activating Proteins
Neurofibromin 1
Insertional Mutagenesis
Extracellular Signal-Regulated MAP Kinases
Guanosine Triphosphate
Drug Resistance
Genes
Hydrolysis
Phosphotransferases
Bone Marrow
Mutation
Therapeutics

ASJC Scopus subject areas

  • General

Cite this

Lauchle, J. O., Kim, D., Le, D. T., Akagi, K., Crone, M., Krisman, K., ... Shannon, K. (2009). Response and resistance to MEK inhibition in leukaemias initiated by hyperactive Ras. Nature, 461(7262), 411-414. https://doi.org/10.1038/nature08279

Response and resistance to MEK inhibition in leukaemias initiated by hyperactive Ras. / Lauchle, Jennifer O.; Kim, Doris; Le, Doan T.; Akagi, Keiko; Crone, Michael; Krisman, Kimberly; Warner, Kegan; Bonifas, Jeannette M.; Li, Qing; Coakley, Kristen M.; Diaz-Flores, Ernesto; Gorman, Matthew; Przybranowski, Sally; Tran, Mary; Kogan, Scott C.; Roose, Jeroen P.; Copeland, Neal G.; Jenkins, Nancy A.; Parada, Luis; Wolff, Linda; Sebolt-Leopold, Judith; Shannon, Kevin.

In: Nature, Vol. 461, No. 7262, 17.09.2009, p. 411-414.

Research output: Contribution to journalArticle

Lauchle, JO, Kim, D, Le, DT, Akagi, K, Crone, M, Krisman, K, Warner, K, Bonifas, JM, Li, Q, Coakley, KM, Diaz-Flores, E, Gorman, M, Przybranowski, S, Tran, M, Kogan, SC, Roose, JP, Copeland, NG, Jenkins, NA, Parada, L, Wolff, L, Sebolt-Leopold, J & Shannon, K 2009, 'Response and resistance to MEK inhibition in leukaemias initiated by hyperactive Ras', Nature, vol. 461, no. 7262, pp. 411-414. https://doi.org/10.1038/nature08279
Lauchle JO, Kim D, Le DT, Akagi K, Crone M, Krisman K et al. Response and resistance to MEK inhibition in leukaemias initiated by hyperactive Ras. Nature. 2009 Sep 17;461(7262):411-414. https://doi.org/10.1038/nature08279
Lauchle, Jennifer O. ; Kim, Doris ; Le, Doan T. ; Akagi, Keiko ; Crone, Michael ; Krisman, Kimberly ; Warner, Kegan ; Bonifas, Jeannette M. ; Li, Qing ; Coakley, Kristen M. ; Diaz-Flores, Ernesto ; Gorman, Matthew ; Przybranowski, Sally ; Tran, Mary ; Kogan, Scott C. ; Roose, Jeroen P. ; Copeland, Neal G. ; Jenkins, Nancy A. ; Parada, Luis ; Wolff, Linda ; Sebolt-Leopold, Judith ; Shannon, Kevin. / Response and resistance to MEK inhibition in leukaemias initiated by hyperactive Ras. In: Nature. 2009 ; Vol. 461, No. 7262. pp. 411-414.
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