A melanocyte lineage program confers resistance to MAP kinase pathway inhibition

1] The Broad Institute of Harvard University and Massachusetts Institute of Technology, 7 Cambridge Center, Cambridge, Massachusetts 02142, USA [2] Department of Medical Oncology, Dana-Farber Cancer Institute, 44 Binney Street, Boston, Massachusetts 02115, USA [3] Harvard Medical School, 25 Shattuck Street, Boston, Massachusetts 02115, USA.
Nature (Impact Factor: 41.46). 11/2013; 504(7478). DOI: 10.1038/nature12688
Source: PubMed


Malignant melanomas harbouring point mutations (Val600Glu) in the serine/threonine-protein kinase BRAF (BRAF(V600E)) depend on RAF-MEK-ERK signalling for tumour cell growth. RAF and MEK inhibitors show remarkable clinical efficacy in BRAF(V600E) melanoma; however, resistance to these agents remains a formidable challenge. Global characterization of resistance mechanisms may inform the development of more effective therapeutic combinations. Here we carried out systematic gain-of-function resistance studies by expressing more than 15,500 genes individually in a BRAF(V600E) melanoma cell line treated with RAF, MEK, ERK or combined RAF-MEK inhibitors. These studies revealed a cyclic-AMP-dependent melanocytic signalling network not previously associated with drug resistance, including G-protein-coupled receptors, adenyl cyclase, protein kinase A and cAMP response element binding protein (CREB). Preliminary analysis of biopsies from BRAF(V600E) melanoma patients revealed that phosphorylated (active) CREB was suppressed by RAF-MEK inhibition but restored in relapsing tumours. Expression of transcription factors activated downstream of MAP kinase and cAMP pathways also conferred resistance, including c-FOS, NR4A1, NR4A2 and MITF. Combined treatment with MAPK-pathway and histone-deacetylase inhibitors suppressed MITF expression and cAMP-mediated resistance. Collectively, these data suggest that oncogenic dysregulation of a melanocyte lineage dependency can cause resistance to RAF-MEK-ERK inhibition, which may be overcome by combining signalling- and chromatin-directed therapeutics.

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    • "Feedback reactivation of the pathway attenuates the inhibitory effects of the drugs (Lito et al., 2012; Poulikakos et al., 2010). Other studies found PTEN and MITF status correlated to response heterogeneity (Johannessen et al., 2013; Paraiso et al., 2011; Xing et al., 2012), but these explain only part of the observed variability. While these factors may contribute to the heterogeneous response, they are limited by characterizing the overall phenotypic response, without distinguishing cytotoxic from cytostatic phenotypes. "
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    ABSTRACT: Graphical Abstract Highlights d Most targets of MAPK pathway are regulated by it only in a subset of cell lines d Cell lines with high activity of IFN pathway are resistant to MEK inhibition d IFNa/b treatment enhances the cytotoxic response of MEK inhibition In Brief Litvin et al. developed a computational method to identify targets of MAPK in melanoma and found that most genes are targets only in a subset of cell lines. They showed that interferon plays an important role in response to MAPK inhibition, and that IFNa/b enhances the effect of MEK inhibition.
    Molecular Cell 04/2015; 57(5):784-796. DOI:10.1016/j.molcel.2014.12.030 · 14.02 Impact Factor
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    • "Sox10 haploinsufficiency in mice can lead to tumour regression in an already established nevus, and in zebrafish, turning off MITF activity in an established melanoma leads to rapid tumour regression (Lister et al., 2014; Shakhova et al., 2012). Furthermore, recent genomic analyses of human melanomas have revealed that MITF and a melanocyte lineage-specific programme are especially important in drug-resistant melanomas, suggesting that MITF is involved in drug-resistance mechanisms (Johannessen et al., 2013). "
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    ABSTRACT: Melanocyte development provides an excellent model for studying more complex developmental processes. Melanocytes have an apparently simple aetiology, differentiating from the neural crest and migrating through the developing embryo to specific locations within the skin and hair follicles, and to other sites in the body. The study of pigmentation mutations in the mouse provided the initial key to identifying the genes and proteins involved in melanocyte development. In addition, work on chicken has provided important embryological and molecular insights, whereas studies in zebrafish have allowed live imaging as well as genetic and transgenic approaches. This cross-species approach is powerful and, as we review here, has resulted in a detailed understanding of melanocyte development and differentiation, melanocyte stem cells and the role of the melanocyte lineage in diseases such as melanoma. © 2015. Published by The Company of Biologists Ltd.
    Development 02/2015; 142(4):620-632. DOI:10.1242/dev.106567 · 6.46 Impact Factor
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    • "In contrast, MEK-independent resistance can develop through overexpression of MITF, which is a transcription factor and regulates melanogenesis,53 activation of PI3K/AKT pathway by loss of PTEN,48 overexpression of receptor tyrosine kinases,54,55 and secretion of hepatocyte growth factor from tumor microenvironment.56 In non-small-cell lung cancer cell lines, selumetinib resistance was mediated by a high level of AKT activity, and the resistance was reversed by AKT inhibition.57 "
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    ABSTRACT: The mitogen-activated protein kinase (MAPK) pathway is a critical oncogenic driver signal in a number of malignancies. The discovery of activating mutations in the MAPK pathway has led to the development of MAPK pathway inhibitors. Selumetinib is a potent and selective inhibitor of MEK1 and MEK2, which are essential downstream molecules in the MAPK pathway. Several preclinical and clinical studies have demonstrated the promising antitumor activity of selumetinib. In this review, we discuss the MAPK pathway in melanoma and summarized data from preclinical and clinical studies of selumetinib for advanced melanoma.
    OncoTargets and Therapy 09/2014; 7:1631-9. DOI:10.2147/OTT.S51596 · 2.31 Impact Factor
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