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.

    • "c-MET and IL-8 (Sanchez-Laorden et al., 2014) were up-expressed, respectively, in 21 of 48 or 44% and 19 of 48 or 40% of resistant tumors. Furthermore , c-FOS and MEOX2 encode tumor cell-intrinsic transcriptional factors implicated in MAPKi resistance (Johannessen et al., 2013). Other purely transcriptomic, highly recurrent GOF events involved the macrophage markers (CD163 and CD163L1). "
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    ABSTRACT: Clinically acquired resistance to MAPK inhibitor (MAPKi) therapies for melanoma cannot be fully explained by genomic mechanisms and may be accompanied by co-evolution of intra-tumoral immunity. We sought to discover non-genomic mechanisms of acquired resistance and dynamic immune compositions by a comparative, transcriptomic-methylomic analysis of patient-matched melanoma tumors biopsied before therapy and during disease progression. Transcriptomic alterations across resistant tumors were highly recurrent, in contrast to mutations, and were frequently correlated with differential methylation of tumor cell-intrinsic CpG sites. We identified in the tumor cell compartment supra-physiologic c-MET up-expression, infra-physiologic LEF1 down-expression and YAP1 signature enrichment as drivers of acquired resistance. Importantly, high intra-tumoral cytolytic T cell inflammation prior to MAPKi therapy preceded CD8 T cell deficiency/exhaustion and loss of antigen presentation in half of disease-progressive melanomas, suggesting cross-resistance to salvage anti-PD-1/PD-L1 immunotherapy. Thus, melanoma acquires MAPKi resistance with highly dynamic and recurrent non-genomic alterations and co-evolving intra-tumoral immunity.
    No preview · Article · Sep 2015 · Cell
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    • "The most recent collection includes 16,100 fully sequenced human ORFs, representing over 13,500 human genes (Yang et al., 2011). Gain-of-function screens using human ORF expression libraries have provided insights into oncogenic RAS signaling and resistance to MAPK pathway inhibition (Johannessen et al., 2013; Shao et al., 2014). "
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    ABSTRACT: Signal transduction pathways activated by receptor tyrosine kinases (RTK) play a critical role in many aspects of cell function. Adaptor proteins serve an important scaffolding function that facilitates key signaling transduction events downstream of RTKs. Recent work integrating both structural and functional genomic approaches has identified several adaptor proteins as new oncogenes. In this review, we focus on the discovery, structure and function, and therapeutic implication of three of these adaptor oncogenes, CRKL, GAB2, and FRS2. Each of the three genes is recurrently amplified in lung adenocarcinoma or ovarian cancer, and is essential to cancer cell lines that harbor such amplification. Overexpression of each gene is able to transform immortalized human cell lines in in vitro or in vivo models. These observations identify adaptor protein as a distinct class of oncogenes and potential therapeutic targets.
    Preview · Article · Sep 2015 · Journal of Genetics and Genomics
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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.
    Full-text · Article · Apr 2015 · Molecular Cell
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