Article

Concurrent loss of the PTEN and RB1 tumor suppressors attenuates RAF dependence in melanomas harboring V600EBRAF

Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
Oncogene (Impact Factor: 8.56). 07/2011; 31(4):446-57. DOI: 10.1038/onc.2011.250
Source: PubMed

ABSTRACT 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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    • "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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    • "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.
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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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