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  • 1
    Publication Date: 2013-01-11
    Description: Mutational activation of BRAF is the most prevalent genetic alteration in human melanoma, with 〉/=50% of tumours expressing the BRAF(V600E) oncoprotein. Moreover, the marked tumour regression and improved survival of late-stage BRAF-mutated melanoma patients in response to treatment with vemurafenib demonstrates the essential role of oncogenic BRAF in melanoma maintenance. However, as most patients relapse with lethal drug-resistant disease, understanding and preventing mechanism(s) of resistance is critical to providing improved therapy. Here we investigate the cause and consequences of vemurafenib resistance using two independently derived primary human melanoma xenograft models in which drug resistance is selected by continuous vemurafenib administration. In one of these models, resistant tumours show continued dependency on BRAF(V600E)--〉MEK--〉ERK signalling owing to elevated BRAF(V600E) expression. Most importantly, we demonstrate that vemurafenib-resistant melanomas become drug dependent for their continued proliferation, such that cessation of drug administration leads to regression of established drug-resistant tumours. We further demonstrate that a discontinuous dosing strategy, which exploits the fitness disadvantage displayed by drug-resistant cells in the absence of the drug, forestalls the onset of lethal drug-resistant disease. These data highlight the concept that drug-resistant cells may also display drug dependency, such that altered dosing may prevent the emergence of lethal drug resistance. Such observations may contribute to sustaining the durability of the vemurafenib response with the ultimate goal of curative therapy for the subset of melanoma patients with BRAF mutations.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3930354/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3930354/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Das Thakur, Meghna -- Salangsang, Fernando -- Landman, Allison S -- Sellers, William R -- Pryer, Nancy K -- Levesque, Mitchell P -- Dummer, Reinhard -- McMahon, Martin -- Stuart, Darrin D -- R01 CA176839/CA/NCI NIH HHS/ -- R01-CA176839/CA/NCI NIH HHS/ -- T32 HL007185/HL/NHLBI NIH HHS/ -- England -- Nature. 2013 Feb 14;494(7436):251-5. doi: 10.1038/nature11814. Epub 2013 Jan 9.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Novartis Institutes for Biomedical Research, Emeryville, California 94608, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23302800" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Disease Models, Animal ; Drug Administration Schedule ; Drug Resistance, Neoplasm/*drug effects ; Extracellular Signal-Regulated MAP Kinases/metabolism ; Humans ; Indoles/*administration & dosage/*adverse effects/pharmacology ; MAP Kinase Signaling System/drug effects ; Melanoma/*drug therapy/genetics/*pathology ; Mice ; Mitogen-Activated Protein Kinase Kinases/metabolism ; Mutation ; Neoplasm Transplantation ; Proto-Oncogene Proteins B-raf/chemistry/genetics/metabolism ; Subcutaneous Tissue ; Sulfonamides/*administration & dosage/*adverse effects/pharmacology ; Time Factors ; Xenograft Model Antitumor Assays
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 2
    Publication Date: 2013-02-09
    Description: Mutations in IDH1 and IDH2, the genes coding for isocitrate dehydrogenases 1 and 2, are common in several human cancers, including leukemias, and result in overproduction of the (R)-enantiomer of 2-hydroxyglutarate [(R)-2HG]. Elucidation of the role of IDH mutations and (R)-2HG in leukemogenesis has been hampered by a lack of appropriate cell-based models. Here, we show that a canonical IDH1 mutant, IDH1 R132H, promotes cytokine independence and blocks differentiation in hematopoietic cells. These effects can be recapitulated by (R)-2HG, but not (S)-2HG, despite the fact that (S)-2HG more potently inhibits enzymes, such as the 5'-methylcytosine hydroxylase TET2, that have previously been linked to the pathogenesis of IDH mutant tumors. We provide evidence that this paradox relates to the ability of (S)-2HG, but not (R)-2HG, to inhibit the EglN prolyl hydroxylases. Additionally, we show that transformation by (R)-2HG is reversible.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3836459/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3836459/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Losman, Julie-Aurore -- Looper, Ryan E -- Koivunen, Peppi -- Lee, Sungwoo -- Schneider, Rebekka K -- McMahon, Christine -- Cowley, Glenn S -- Root, David E -- Ebert, Benjamin L -- Kaelin, William G Jr -- P30 DK049216/DK/NIDDK NIH HHS/ -- R01 CA068490/CA/NCI NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2013 Mar 29;339(6127):1621-5. doi: 10.1126/science.1231677. Epub 2013 Feb 7.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23393090" target="_blank"〉PubMed〈/a〉
    Keywords: Cell Line, Tumor ; Cell Transformation, Neoplastic/genetics/*metabolism ; Glutarates/*metabolism ; *Hematopoiesis ; Humans ; Isocitrate Dehydrogenase/genetics/*metabolism ; Leukemia/*enzymology/genetics ; Models, Biological ; Procollagen-Proline Dioxygenase/*antagonists & inhibitors
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 3
    Publication Date: 2012-11-06
    Description: People with pale skin, red hair, freckles and an inability to tan--the 'red hair/fair skin' phenotype--are at highest risk of developing melanoma, compared to all other pigmentation types. Genetically, this phenotype is frequently the product of inactivating polymorphisms in the melanocortin 1 receptor (MC1R) gene. MC1R encodes a cyclic AMP-stimulating G-protein-coupled receptor that controls pigment production. Minimal receptor activity, as in red hair/fair skin polymorphisms, produces the red/yellow pheomelanin pigment, whereas increasing MC1R activity stimulates the production of black/brown eumelanin. Pheomelanin has weak shielding capacity against ultraviolet radiation relative to eumelanin, and has been shown to amplify ultraviolet-A-induced reactive oxygen species. Several observations, however, complicate the assumption that melanoma risk is completely ultraviolet-radiation-dependent. For example, unlike non-melanoma skin cancers, melanoma is not restricted to sun-exposed skin and ultraviolet radiation signature mutations are infrequently oncogenic drivers. Although linkage of melanoma risk to ultraviolet radiation exposure is beyond doubt, ultraviolet-radiation-independent events are likely to have a significant role. Here we introduce a conditional, melanocyte-targeted allele of the most common melanoma oncoprotein, BRAF(V600E), into mice carrying an inactivating mutation in the Mc1r gene (these mice have a phenotype analogous to red hair/fair skin humans). We observed a high incidence of invasive melanomas without providing additional gene aberrations or ultraviolet radiation exposure. To investigate the mechanism of ultraviolet-radiation-independent carcinogenesis, we introduced an albino allele, which ablates all pigment production on the Mc1r(e/e) background. Selective absence of pheomelanin synthesis was protective against melanoma development. In addition, normal Mc1r(e/e) mouse skin was found to have significantly greater oxidative DNA and lipid damage than albino-Mc1r(e/e) mouse skin. These data suggest that the pheomelanin pigment pathway produces ultraviolet-radiation-independent carcinogenic contributions to melanomagenesis by a mechanism of oxidative damage. Although protection from ultraviolet radiation remains important, additional strategies may be required for optimal melanoma prevention.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3521494/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3521494/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Mitra, Devarati -- Luo, Xi -- Morgan, Ann -- Wang, Jin -- Hoang, Mai P -- Lo, Jennifer -- Guerrero, Candace R -- Lennerz, Jochen K -- Mihm, Martin C -- Wargo, Jennifer A -- Robinson, Kathleen C -- Devi, Suprabha P -- Vanover, Jillian C -- D'Orazio, John A -- McMahon, Martin -- Bosenberg, Marcus W -- Haigis, Kevin M -- Haber, Daniel A -- Wang, Yinsheng -- Fisher, David E -- 5R01 AR043369-16/AR/NIAMS NIH HHS/ -- F30 ES020663-01/ES/NIEHS NIH HHS/ -- R01 AR043369/AR/NIAMS NIH HHS/ -- R01 CA101864/CA/NCI NIH HHS/ -- R01 CA129933/CA/NCI NIH HHS/ -- R01 CA131075/CA/NCI NIH HHS/ -- R01 CA176839/CA/NCI NIH HHS/ -- R01-CA101864/CA/NCI NIH HHS/ -- T32 GM007753/GM/NIGMS NIH HHS/ -- England -- Nature. 2012 Nov 15;491(7424):449-53. doi: 10.1038/nature11624. Epub 2012 Oct 31.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Cutaneous Biology Research Center, Massachusetts General Hospital, Charlestown, Massachusetts 02129, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23123854" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Gene Expression Regulation/drug effects ; Hair Color/*genetics ; Indoles/pharmacology ; Melanins/metabolism ; Melanoma/*genetics ; Mice ; Mice, Inbred C57BL ; Monophenol Monooxygenase/genetics ; Peroxidases/metabolism ; Protein Kinase Inhibitors/pharmacology ; Proto-Oncogene Proteins B-raf/genetics ; Receptor, Melanocortin, Type 1/genetics ; Skin Pigmentation/*genetics ; Sulfonamides/pharmacology ; Survival Analysis ; Tumor Cells, Cultured ; *Ultraviolet Rays
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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