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.

Download full-text


Available from: David Cobrinik
  • Source
    • "An excellent example was recently published in the open-access journal eLife. The authors followed previous work in which they had screened 149 melanoma cell lines to identify BRAF V600E mutated cells that were resistant to inhibition of the downstream MEK protein (Xing et al., 2012). Thus, although these cells had a BRAF-dependent activation of the MAPK pathway, they did not require MEK phosphorylation for growth. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The recent convergence of high-dimensional molecular datasets with small-molecule inhibitor pipelines allows for selective targeting of aberrantly regulated pathways in many cancer types. But intra-tumor heterogeneity, paradoxical activation, intrinsic or acquired therapeutic resistance, and non-linear pathway interactions confound most simple targeting strategies(Widmer et al., 2015). For instance, MAPK signaling is activated by hot-spot mutations in BRAF, which are found in about 40-50% of melanoma cases. This article is protected by copyright. All rights reserved.
    Full-text · Article · Oct 2015 · Pigment Cell & Melanoma Research
  • Source
    • "Resistance to vemurafenib emerges after a period of ∼7 months in tumors that initially responded to single-agent therapy (Chapman et al., 2011; Sosman et al., 2012). Multiple RAFi and MEKi (e.g., PD-0325901, Trametinib) resistance mechanisms, which may involve alterations in NRAS/ERK pathway (e.g., NRAS mutations, switching between RAF isoforms) or parallel pathways (e.g., PTEN loss), have been discovered in melanoma (Johannessen et al., 2010; Nazarian et al., 2010; Poulikakos et al., 2010; Xing et al., 2012). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Resistance to targeted cancer therapies is an important clinical problem. The discovery of anti-resistance drug combinations is challenging as resistance can arise by diverse escape mechanisms. To address this challenge, we improved and applied the experimental-computational perturbation biology method. Using statistical inference, we build network models from high-throughput measurements of molecular and phenotypic responses to combinatorial targeted perturbations. The models are computationally executed to predict the effects of thousands of untested perturbations. In RAF-inhibitor resistant melanoma cells, we measured 143 proteomic/phenotypic entities under 89 perturbation conditions and predicted c-Myc as an effective therapeutic co-target with BRAF or MEK. Experiments using the BET bromodomain inhibitor JQ1 affecting the level of c-Myc protein and protein kinase inhibitors targeting the ERK pathway confirmed the prediction. In conclusion, we propose an anti-cancer strategy of co-targeting a specific upstream alteration and a general downstream point of vulnerability to prevent or overcome resistance to targeted drugs. DOI: 10.7554/eLife.04640.001
    Full-text · Article · Aug 2015 · eLife Sciences
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    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
Show more