MEK inhibition exhibits efficacy in human and mouse neurofibromatosis tumors

The Journal of clinical investigation (Impact Factor: 13.22). 12/2012; 123(1). DOI: 10.1172/JCI60578
Source: PubMed


Neurofibromatosis type 1 (NF1) patients develop benign neurofibromas and malignant peripheral nerve sheath tumors (MPNST). These incurable peripheral nerve tumors result from loss of NF1 tumor suppressor gene function, causing hyperactive Ras signaling. Activated Ras controls numerous downstream effectors, but specific pathways mediating the effects of hyperactive Ras in NF1 tumors are unknown. We performed cross-species transcriptome analyses of mouse and human neurofibromas and MPNSTs and identified global negative feedback of genes that regulate Ras/Raf/MEK/ERK signaling in both species. Nonetheless, ERK activation was sustained in mouse and human neurofibromas and MPNST. We used a highly selective pharmacological inhibitor of MEK, PD0325901, to test whether sustained Ras/Raf/MEK/ERK signaling contributes to neurofibroma growth in a neurofibromatosis mouse model (Nf1fl/fl;Dhh-Cre) or in NF1 patient MPNST cell xenografts. PD0325901 treatment reduced aberrantly proliferating cells in neurofibroma and MPNST, prolonged survival of mice implanted with human MPNST cells, and shrank neurofibromas in more than 80% of mice tested. Our data demonstrate that deregulated Ras/ERK signaling is critical for the growth of NF1 peripheral nerve tumors and provide a strong rationale for testing MEK inhibitors in NF1 clinical trials.

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Available from: Eva Dombi, Nov 10, 2014
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    • "While Twist1 is largely absent from adult differentiated tissues, it is expressed in diseased heart valves and highly metastatic cancers such as breast, pancreatic, gastric, prostate, and malignant peripheral nerve sheath tumors (MPNST) [6, 7, 13, 14]. Human MPNST cells can harbor NF1 and p53 mutations, and murine NF1 and p53 mutations can cause similar nerve-associated sarcomas, peripheral nerve sheath tumors (PNST) [14–16]. siRNA-mediated knockdown of Twist1 abrogates the migratory activity of human MPNST cells in vitro [14, 16]. "
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    ABSTRACT: The basic helix-loop-helix transcription factor Twist1 has well-documented roles in progenitor populations of the developing embryo, including endocardial cushions (ECC) and limb buds, and also in cancer. Whether Twist1 regulates the same transcriptional targets in different tissue types is largely unknown. The tissue-specificity of Twist1 genomic occupancy was examined in mouse ECCs, limb buds, and peripheral nerve sheath tumor (PNST) cells using chromatin immunoprecipitation followed by sequencing (Chip-seq) analysis. Consistent with known Twist1 functions during development and in cancer cells, Twist1-DNA binding regions associated with genes related to cell migration and adhesion were detected in all three tissues. However, the vast majority of Twist1 binding regions were specific to individual tissue types. Thus, while Twist1 has similar functions in ECCs, limb buds, and PNST cells, the specific genomic sequences occupied by Twist1 were different depending on cellular context. Subgroups of shared genes, also predominantly related to cell adhesion and migration, were identified in pairwise comparisons of ECC, limb buds and PNST cells. Twist1 genomic occupancy was detected for six binding regions in all tissue types, and Twist1-binding sequences associated with Chst11, Litaf, Ror2, and Spata5 also bound the potential Twist1 cofactor RREB1. Pathway analysis of the genes associated with Twist1 binding suggests that Twist1 may regulate genes associated with the Wnt signaling pathway in ECCs and limb buds. Together, these data indicate that Twist1 interacts with genes that regulate adhesion and migration in different tissues, potentially through distinct sets of target genes. In addition, there is a small subset of genes occupied by Twist1 in all three tissues that may represent a core group of Twist1 target genes in multiple cell types.
    BMC Genomics 09/2014; 15(1):821. DOI:10.1186/1471-2164-15-821 · 3.99 Impact Factor
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    • "On the basis of the finding that B16BR cells maintain refractory MEK activity, we supposed that combined inhibition of AAG8 and MEK could limit B16BR cell growth more efficiently. Substantiating this conjecture, we combined BD1047 and PD901 (hereafter PD901), a selective MEK inhibitor currently in clinical cancer trials which blocks MEK1 at values of 1 μmol/L in vitro 26. However, MEK inhibitors have often been reported for drug resistance and dose-limiting side effects, resulting in the compromised efficacy 19. "
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    ABSTRACT: Drug resistance presents a challenge to the treatment of cancer patients, especially for melanomas, most of which are caused by the hyperactivation of MAPK signaling pathway. Innate or acquired drug-resistant relapse calls for the investigation of the resistant mechanisms and new anti-cancer drugs to provide implications for the ultimate goal of curative therapy. Aging-associated gene 8 (AAG8, encoded by the SIGMAR1 gene) is a chaperone protein profoundly elaborated in neurology. However, roles of AAG8 in carcinogenesis remain unclear. Herein, we discover AAG8 antagonists as new MEK inhibitors in melanoma cells and propose a novel drug combination strategy for melanoma therapy by presenting the experimental evidences. We report that specific antagonism of AAG8, efficiently suppresses melanoma cell growth and migration through, at least in part, the inactivation of the RAS-CRAF-MEK signaling pathway. We further demonstrate that melanoma cells that are resistant to AAG8 antagonist harbor refractory CRAF-MEK activity. MEK acts as a central mediator for anti-cancer effects and also for the resistance mechanism, leading to our proposal of tandem AAG8-MEK inhibition in melanoma cells. Combination of AAG8 antagonist and very low concentration of a MEK inhibitor synergistically restricts the growth of drug-resistant cells. These data collectively pinpoint AAG8 as a potential target and delineate a promising drug combination strategy for melanoma therapy.
    Cancer Medicine 06/2014; 3(3). DOI:10.1002/cam4.233 · 2.50 Impact Factor
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    • "Nowadays, the therapy of NF patients is the surgical removal of neurofibromas and the treatment of the disease-associated clinical features. There are some experimental results and drug developments with growth factors and tyrosine-kinase and oncogenic kinase inhibitors (Jouhilahti et al. 2011; Farrer et al. 2013; Jessen et al. 2013; Maruta 2011). In case of the best efficient application of these medications , it is important to know the exact and detailed genetic background of each NF patient. "
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    ABSTRACT: Neurofibromatosis type 1 (NF1) gene exhibits one of the highest spontaneous mutation rates in the human genome. Identification of the NF1 mutation is challenging because the NF1 gene is very large and complex, lacking mutational "hot spots." There is no clustering of mutations, there are several pseudogenes, and a wide spectrum of different types of mutation has been recognized. To date, NF1 mutations or deleted regions have been detected with a number of techniques. With the appearance of next-generation sequencing (NGS) machines, molecular biology is in a new revolutionary phase. Our aim was to work out a method to use the high-throughput NGS machine, Ion Torrent PGM, in diagnostic settings for neurofibromatosis type 1. In our examination, we could reveal 21 distinct variations in NF1 gene in seven patients. This is an absolutely new method for exploring the genetic background of neurofibromatosis type 1 exhibiting the extremely high throughput of NGS in a diagnostic setting.
    Journal of Molecular Neuroscience 03/2014; 53(2). DOI:10.1007/s12031-014-0286-7 · 2.34 Impact Factor
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