Article

Response and Resistance to MEK Inhibition in Leukaemias Initiated by Hyperactive Ras

Department of Pediatrics, University of California, San Francisco, California 94143, USA.
Nature (Impact Factor: 42.35). 10/2009; 461(7262):411-4. DOI: 10.1038/nature08279
Source: PubMed

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.

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Available from: Kimberly Krisman, Feb 17, 2014
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    • "Resistance mechanisms vary considerably and include mutations blocking drug-target interaction, genetic alterations sustaining signaling in downstream pathways , or alternate survival pathways (Torti and Trusolino, 2011; Berns and Bernards, 2012). The pervasive disease recurrence following targeted therapy has motivated the use of inducible driver oncogene GEM models of cancers to proactively illuminate potential mechanisms of resistance employed by human cancers (Lauchle et al., 2009). Given the essential roles of oncogenic Kras in both PDAC initiation and maintenance, mutant KRAS and its signaling pathways have been a major focus for the development of disease models for human PDAC (Hingorani et al., 2003; Collisson et al., 2012; Collins et al., 2012; Ying et al., 2012; Eser et al., 2013; Guerra and Barbacid, 2013). "
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    • "The notion that neurofibromin loss has cell type-specific effects on intracellular pathway signaling is underscored by several observations. While neurofibromin primarily regulates astrocyte and Schwann cell growth in a RAS/Akt/mTOR-dependent manner (Banerjee et al., 2010; Johannessen et al., 2005; Johansson et al., 2008; Sandsmark et al., 2007), RAS/MAPK appears to be the major neurofibromin growth control pathway in leukemic cells (Lauchle et al., 2009). Similarly, neuronal differentiation from neural stem cells (NSCs) is dependent on neurofibromin cAMP signaling, while astrocyte differentiation from NSCs requires RAS/ Akt signaling (Hegedus et al., 2007). "
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    • "Transposons and retroviruses are widely used in insertional mutagenesis (IM) screens in mice to discover candidate cancer genes (Collier et al. 2005; Dupuy et al. 2005, 2009; Theodorou et al. 2007; Keng et al. 2009; Starr et al. 2009; Copeland and Jenkins 2010; Rad et al. 2010). IM screens have also been instrumental for the identification of genetic interactions between genes driving tumor evolution (Uren et al. 2008; Kool and Berns 2009; Kool et al. 2010) and for the identification of genes that confer resistance to anticancer drugs (Lauchle et al. 2009) or pathogens (Carette et al. 2009). Finally, retroviruses and transposons are used for germline mutagenesis in a range of experimental organisms (Amsterdam et al. 1999; Golling et al. 2002; Ding et al. 2005; Keng et al. 2005; de Wit et al. 2010). "
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