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 language | English (US) |
|---|---|
| Pages (from-to) | 411-414 |
| Number of pages | 4 |
| Journal | Nature |
| Volume | 461 |
| Issue number | 7262 |
| DOIs | |
| State | Published - Sep 17 2009 |
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Cite this
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 journal › Article
}
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
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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UR - http://www.scopus.com/inward/citedby.url?scp=70349273655&partnerID=8YFLogxK
U2 - 10.1038/nature08279
DO - 10.1038/nature08279
M3 - Article
VL - 461
SP - 411
EP - 414
JO - Nature
JF - Nature
SN - 0028-0836
IS - 7262
ER -