Xing F, Persaud Y, Pratilas CA et al.Concurrent loss of the PTEN and RB1 tumor suppressors attenuates RAF dependence in melanomas harboring (V600E)BRAF. Oncogene 31:446-457

Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
Oncogene (Impact Factor: 8.46). 07/2011; 31(4):446-57. DOI: 10.1038/onc.2011.250
Source: PubMed


Identifying the spectrum of genetic alterations that cooperate with critical oncogenes to promote transformation provides a foundation for understanding the diversity of clinical phenotypes observed in human cancers. Here, we performed integrated analyses to identify genomic alterations that co-occur with oncogenic BRAF in melanoma and abrogate cellular dependence upon this oncogene. We identified concurrent mutational inactivation of the PTEN and RB1 tumor suppressors as a mechanism for loss of BRAF/MEK dependence in melanomas harboring (V600E)BRAF mutations. RB1 alterations were mutually exclusive with loss of p16(INK4A), suggesting that whereas p16(INK4A) and RB1 may have overlapping roles in preventing tumor formation, tumors with loss of RB1 exhibit diminished dependence upon BRAF signaling for cell proliferation. These findings provide a genetic basis for the heterogeneity of clinical outcomes in patients treated with targeted inhibitors of the mitogen-activated protein kinase pathway. Our results also suggest a need for comprehensive screening for RB1 and PTEN inactivation in patients treated with RAF and MEK-selective inhibitors to determine whether these alterations are associated with diminished clinical benefit in patients whose cancers harbor mutant BRAF.

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Available from: David Cobrinik, Oct 11, 2015
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    • "The cell lines display a wide range of cytotoxic responses , as well as differences in proliferation under MEK inhibition (Figures 1B and 1C). Notably, and contrary to previously published results (Barretina et al., 2012; Xing et al., 2012), we found that key genetic aberrations common in melanoma, including MITF and PTEN status, and MAPK mutation type, fail to fully explain the response heterogeneity (Figures 1B, S1C, and S1D). "
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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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    • "Although many of these studies show promise in vitro (Table 1), their utility in patients is often burdened by toxicity issues. Xing et al. (2012) were able to demonstrate a synergism associated with melanoma apoptosis when combining a MEK inhibitor with a phosphatidylinositide 3-kinase inhibitor. Furthermore, a recent phase II study of the MEK inhibitor, selumetinib, found that a low patient response rate is associated with high basal levels of phosphoAKT (Catalanotti et al., 2013). "
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    ABSTRACT: In early 2011, we reviewed the initial success of the RAF inhibitor vemurafenib in mutant V600 BRAF melanoma patients. It was soon evident that the response to RAF inhibitor is heterogeneous and that the short-term benefits are burdened by the development of resistance. The field has progressed rapidly with the Food and Drug Administration approval of vemurafenib and the development of other RAF and MEK (mitogen-activated protein kinase/extracellular signal-regulated kinase) inhibitors. Despite these advances, the issue of RAF inhibitor resistance remains. Here, we review recent clinical advances in the field, the growing number of resistance mechanisms, preclinical evidence for combinatorial trials using RAF inhibitors as the building blocks, and the new challenges that are arising.Journal of Investigative Dermatology advance online publication, 10 October 2013; doi:10.1038/jid.2013.358.
    Journal of Investigative Dermatology 10/2013; 134(2). DOI:10.1038/jid.2013.358 · 7.22 Impact Factor
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    • "BRAF and RAS mutations mediate resistance to AKT targeted agents [23]. Alternatively, drug combinations that inhibit both pathways may be more clinically effective for tumors with evidence of dual pathway activation, including those with RTK mutation/activation [27], [32], other genetic alterations of the pathway (RAS, PIK3CA, BRAF mutations and/or PTEN loss) [23], [28], [33]–[37], or simply expression of phosphorylated AKT or ERK [31], [38]. "
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    ABSTRACT: Uveal melanomas possess activation of the mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K)/AKT/mammalian Target of Rapamycin (mTOR) pathways. MAPK activation occurs via somatic mutations in the heterotrimeric G protein subunits GNAQ and GNA11 for over 70% of tumors and less frequently via V600E BRAF mutations. In this report, we describe the impact of dual pathway inhibition upon uveal melanoma cell lines with the MEK inhibitor selumetinib (AZD6244/ARRY-142886) and the ATP-competitive mTOR kinase inhibitor AZD8055. While synergistic reductions in cell viability were observed with AZD8055/selumetinib in both BRAF and GNAQ mutant cell lines, apoptosis was preferentially induced in BRAF mutant cells only. In vitro apoptosis assay results were predictive of in vivo drug efficacy as tumor regressions were observed only in a BRAF mutant xenograft model, but not GNAQ mutant model. We went on to discover that GNAQ promotes relative resistance to AZD8055/selumetinib-induced apoptosis in GNAQ mutant cells. For BRAF mutant cells, both AKT and 4E-BP1 phosphorylation were modulated by the combination; however, decreasing AKT phosphorylation alone was not sufficient and decreasing 4E-BP1 phosphorylation was not required for apoptosis. Instead, cooperative mTOR complex 2 (mTORC2) and MEK inhibition resulting in downregulation of the pro-survival protein MCL-1 was found to be critical for combination-induced apoptosis. These results suggest that the clinical efficacy of combined MEK and mTOR kinase inhibition will be determined by tumor genotype, and that BRAF mutant malignancies will be particularly susceptible to this strategy.
    PLoS ONE 07/2012; 7(7):e40439. DOI:10.1371/journal.pone.0040439 · 3.23 Impact Factor
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