title: Response and resistance to MEK inhibition in leukaemias initiated by hyperactive Ras.
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 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 p38alpha. 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.
authors.affiliation: Department of Pediatrics, University of California, San Francisco, California 94143, USA.
authors.forename: Jennifer O
authors.initials: JO
authors.lastname: Lauchle
authors.forename: Doris
authors.initials: D
authors.lastname: Kim
authors.forename: Doan T
authors.initials: DT
authors.lastname: Le
authors.forename: Keiko
authors.initials: K
authors.lastname: Akagi
authors.forename: Michael
authors.initials: M
authors.lastname: Crone
authors.forename: Kimberly
authors.initials: K
authors.lastname: Krisman
authors.forename: Kegan
authors.initials: K
authors.lastname: Warner
authors.forename: Jeannette M
authors.initials: JM
authors.lastname: Bonifas
authors.forename: Qing
authors.initials: Q
authors.lastname: Li
authors.forename: Kristen M
authors.initials: KM
authors.lastname: Coakley
authors.forename: Ernesto
authors.initials: E
authors.lastname: Diaz-Flores
authors.forename: Matthew
authors.initials: M
authors.lastname: Gorman
authors.forename: Sally
authors.initials: S
authors.lastname: Przybranowski
authors.forename: Mary
authors.initials: M
authors.lastname: Tran
authors.forename: Scott C
authors.initials: SC
authors.lastname: Kogan
authors.forename: Jeroen P
authors.initials: JP
authors.lastname: Roose
authors.forename: Neal G
authors.initials: NG
authors.lastname: Copeland
authors.forename: Nancy A
authors.initials: NA
authors.lastname: Jenkins
authors.forename: Luis
authors.initials: L
authors.lastname: Parada
authors.forename: Linda
authors.initials: L
authors.lastname: Wolff
authors.forename: Judith
authors.initials: J
authors.lastname: Sebolt-Leopold
authors.forename: Kevin
authors.initials: K
authors.lastname: Shannon
mesh_terms: D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D011905:Genes, ras; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D048308:Mitogen-Activated Protein Kinase 14 / Q000235:genetics / Q000378:metabolism; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C120227:2-(2-chloro-4-iodophenylamino)-N-cyclopropylmethoxy-3,4-difluorobenzamide; D001549:Benzamides; D020662:Guanine Nucleotide Exchange Factors; C112278:Rasgrp1 protein, mouse; D048308:Mitogen-Activated Protein Kinase 14; D020929:Mitogen-Activated Protein Kinase Kinases; D018631:ras Proteins