TY - JOUR
T1 - Response and resistance to MEK inhibition in leukaemias initiated by hyperactive Ras
AU - Lauchle, Jennifer O.
AU - Kim, Doris
AU - Le, Doan T.
AU - Akagi, Keiko
AU - Crone, Michael
AU - Krisman, Kimberly
AU - Warner, Kegan
AU - Bonifas, Jeannette M.
AU - Li, Qing
AU - Coakley, Kristen M.
AU - Diaz-Flores, Ernesto
AU - Gorman, Matthew
AU - Przybranowski, Sally
AU - Tran, Mary
AU - Kogan, Scott C.
AU - Roose, Jeroen P.
AU - Copeland, Neal G.
AU - Jenkins, Nancy A.
AU - Parada, Luis
AU - Wolff, Linda
AU - Sebolt-Leopold, Judith
AU - Shannon, Kevin
N1 - Funding Information:
Acknowledgements 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.
PY - 2009/9/17
Y1 - 2009/9/17
N2 - 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.
AB - 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.
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U2 - 10.1038/nature08279
DO - 10.1038/nature08279
M3 - Article
C2 - 19727076
AN - SCOPUS:70349273655
VL - 461
SP - 411
EP - 414
JO - Nature
JF - Nature
SN - 0028-0836
IS - 7262
ER -