Article

BRAF mutation predicts sensitivity to MEK inhibition.

Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10021, USA.
Nature (Impact Factor: 42.35). 02/2006; 439(7074):358-62. DOI: 10.1038/nature04304
Source: PubMed

ABSTRACT The kinase pathway comprising RAS, RAF, mitogen-activated protein kinase kinase (MEK) and extracellular signal regulated kinase (ERK) is activated in most human tumours, often through gain-of-function mutations of RAS and RAF family members. Using small-molecule inhibitors of MEK and an integrated genetic and pharmacologic analysis, we find that mutation of BRAF is associated with enhanced and selective sensitivity to MEK inhibition when compared to either 'wild-type' cells or cells harbouring a RAS mutation. This MEK dependency was observed in BRAF mutant cells regardless of tissue lineage, and correlated with both downregulation of cyclin D1 protein expression and the induction of G1 arrest. Pharmacological MEK inhibition completely abrogated tumour growth in BRAF mutant xenografts, whereas RAS mutant tumours were only partially inhibited. These data suggest an exquisite dependency on MEK activity in BRAF mutant tumours, and offer a rational therapeutic strategy for this genetically defined tumour subtype.

0 Bookmarks
 · 
173 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Background: Inhibition of mitogen-activated protein kinase (MEK, also known as MAPK2, MAPKK), a key molecule of the Ras/MAPK (mitogen-activated protein kinase) pathway, has shown promising effects on B-raf-mutated and some RAS (rat sarcoma)-activated tumors in clinical trials. The objective of this study is to examine the efficacy of a novel allosteric MEK inhibitor RO4987655 in K-ras-mutated human tumor xenograft models using [ 18 F] FDG-PET imaging and proteomics technology. Methods: [ 18 F] FDG uptake was studied in human lung carcinoma xenografts from day 0 to day 9 of RO4987655 therapy using microPET Focus 120 (CTI Concorde Microsystems, Knoxville, TN, USA). The expression levels of GLUT1 and hexokinase 1 were examined using semi-quantitative fluorescent immunohistochemistry (fIHC). The in vivo effects of RO4987655 on MAPK/PI3K pathway components were assessed by reverse phase protein arrays (RPPA).
    EJNMMI Research. 09/2014; 4(34).
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: A disruptive approach to therapeutic discovery and development is required in order to significantly improve the success rate of drug discovery for central nervous system (CNS) disorders. In this review, we first assess the key factors contributing to the frequent clinical failures for novel drugs. Second, we discuss cancer translational research paradigms that addressed key issues in drug discovery and development and have resulted in delivering drugs with significantly improved outcomes for patients. Finally, we discuss two emerging technologies that could improve the success rate of CNS therapies: human induced pluripotent stem cell (hiPSC)-based studies and multiscale biology models. Coincident with advances in cellular technologies that enable the generation of hiPSCs directly from patient blood or skin cells, together with methods to differentiate these hiPSC lines into specific neural cell types relevant to neurological disease, it is also now possible to combine data from large-scale forward genetics and post-mortem global epigenetic and expression studies in order to generate novel predictive models. The application of systems biology approaches to account for the multiscale nature of different data types, from genetic to molecular and cellular to clinical, can lead to new insights into human diseases that are emergent properties of biological networks, not the result of changes to single genes. Such studies have demonstrated the heterogeneity in etiological pathways and the need for studies on model systems that are patient-derived and thereby recapitulate neurological disease pathways with higher fidelity. In the context of two common and presumably representative neurological diseases, the neurodegenerative disease Alzheimer's Disease, and the psychiatric disorder schizophrenia, we propose the need for, and exemplify the impact of, a multiscale biology approach that can integrate panomic, clinical, imaging, and literature data in order to construct predictive disease network models that can (i) elucidate subtypes of syndromic diseases, (ii) provide insights into disease networks and targets and (iii) facilitate a novel drug screening strategy using patient-derived hiPSCs to discover novel therapeutics for CNS disorders.
    Frontiers in Pharmacology 12/2014; 5:252.
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Oncology is one of the most important fields of personalized medicine as a majority of efforts in this field have recently centered on targeted cancer drug development. New tools are continuously being developed that promise to make cancer treatment more efficacious while causing fewer side effects. Like most industries, the biopharmaceutical industry is also following certain global trends and these are analyzed in this article. As academia and industry are mutually dependent on each other, researchers in the field should be aware of those trends and the immediate consequences for their research. It is important for the future of this field that there is a healthy relationship among all interested parties as the challenges of personalized medicine are becoming ever more complex.
    Journal of personalized medicine. 01/2012; 2(1):15-34.

Full-text (2 Sources)

Download
9 Downloads
Available from
May 20, 2014