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


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 suppressor1,2. 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 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.

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Figure 1: Retroviral mutagenesis induces AML in Mx1-Cre, Nf1 flox/flox mice and alters response to MEK inhibition.
Figure 2: Response and resistance to CI-1040 in Mx1-Cre, Nf1 flox/flox mice with AML.
Figure 3: Genetic and functional analysis implicates Rasgrp1 overexpression as a resistance mechanism in AML 6554.
Figure 4: Genetic and functional analysis of AML 6537 associates reduced p38α kinase activity with resistance to MEK inhibition.


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We are grateful to B. Braun, J. Downing, S. Lowe and C. Sawyers for discussion and advice throughout the project. We are thankful for C. Hartzell for studies on RasGRP protein expression. This work was supported by National Institutes of Health grants U01 CA84221, R37 CA72614, T32 CA09043, T32 HD044331 and K08 CA119105, by a Specialized Center of Research award from the Leukemia and Lymphoma Society (LLS 7019-04), by the US Army Neurofibromatosis Research Program (Project DAMD 17-02-1-0638), by the Ronald McDonald House Charities of Southern California/Couples Against Leukemia, by the Jeffrey and Karen Peterson Family Foundation and by the Frank A. Campini Foundation. S.C.K. is a Scholar of the Leukemia and Lymphoma Society of America. J.P.R. is a Kimmel Foundation Scholar. The Intramural Research Program of the National Cancer Institute’s Center for Cancer Research supports research in the laboratory of L.W. at the National Institutes of Health.

Author Contributions J.O.L and K.S. designed and performed experiments, analysed data and wrote the paper. D.K., D.T.L., M.C., K.K., K.W. and J.M.B. designed experiments, conducted studies, analysed data and provided input to the manuscript. K.A. performed bioinformatics analysis of retroviral insertion sequences. Q.L., K.M.C., E.D.-F., M.G. and M.T. designed and conducted experiments. J.P.R. provided critical reagents, assisted in experimental design and edited the manuscript. N.C., N.J. and L.W. provided retroviral reagents and training in experimental protocols. L.P. provided the mouse strain and input into the manuscript. J.S.-L. and S.P. developed protocols for suspending and administering the MEK inhibitor and provided the drug used in all studies.

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Correspondence to Kevin Shannon.

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Lauchle, J., Kim, D., Le, D. et al. Response and resistance to MEK inhibition in leukaemias initiated by hyperactive Ras. Nature 461, 411–414 (2009).

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