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Differential chemosensitivity to antifolate drugs between RAS and BRAF melanoma cells.
Arozarena, Imanol; Goicoechea, Ibai; Erice, Oihane; Ferguson, Jennnifer; Margison, Geoffrey P; Wellbrock, Claudia.
Afiliación
  • Arozarena I; Manchester Cancer Research Centre, The University of Manchester, Michael Smith Building, Oxford Road, Manchester M13 9PT, UK. Imanol.Arozarena@manchester.ac.uk.
Mol Cancer ; 13: 154, 2014 Jun 19.
Article en En | MEDLINE | ID: mdl-24941944
BACKGROUND: The importance of the genetic background of cancer cells for the individual susceptibility to cancer treatments is increasingly apparent. In melanoma, the existence of a BRAF mutation is a main predictor for successful BRAF-targeted therapy. However, despite initial successes with these therapies, patients relapse within a year and have to move on to other therapies. Moreover, patients harbouring a wild type BRAF gene (including 25% with NRAS mutations) still require alternative treatment such as chemotherapy. Multiple genetic parameters have been associated with response to chemotherapy, but despite their high frequency in melanoma nothing is known about the impact of BRAF or NRAS mutations on the response to chemotherapeutic agents. METHODS: Using cell proliferation and DNA methylation assays, FACS analysis and quantitative-RT-PCR we have characterised the response of a panel of NRAS and BRAF mutant melanoma cell lines to various chemotherapy drugs, amongst them dacarbazine (DTIC) and temozolomide (TMZ) and DNA synthesis inhibitors. RESULTS: Although both, DTIC and TMZ act as alkylating agents through the same intermediate, NRAS and BRAF mutant cells responded differentially only to DTIC. Further analysis revealed that the growth-inhibitory effects mediated by DTIC were rather due to interference with nucleotide salvaging, and that NRAS mutant melanoma cells exhibit higher activity of the nucleotide synthesis enzymes IMPDH and TK1. Importantly, the enhanced ability of RAS mutant cells to use nucleotide salvaging resulted in resistance to DHFR inhibitors. CONCLUSION: In summary, our data suggest that the genetic background in melanoma cells influences the response to inhibitors blocking de novo DNA synthesis, and that defining the RAS mutation status could be used to stratify patients for the use of antifolate drugs.
Asunto(s)

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias Cutáneas / Proteínas Proto-Oncogénicas B-raf / GTP Fosfohidrolasas / Melanoma / Proteínas de la Membrana Límite: Humans Idioma: En Revista: Mol Cancer Asunto de la revista: NEOPLASIAS Año: 2014 Tipo del documento: Article Pais de publicación: Reino Unido

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias Cutáneas / Proteínas Proto-Oncogénicas B-raf / GTP Fosfohidrolasas / Melanoma / Proteínas de la Membrana Límite: Humans Idioma: En Revista: Mol Cancer Asunto de la revista: NEOPLASIAS Año: 2014 Tipo del documento: Article Pais de publicación: Reino Unido