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Title

Individualized strategies to target specific mechanisms of disease in malignant melanoma patients displaying unique mutational signatures

AuthorsCuriel-Olmo, Soraya; Vidal, Rebeca CSIC ORCID; Varela, Ignacio CSIC ORCID; Moreno, Thaidy; Madureira, Rebeca CSIC; Valdizán, Elsa M. CSIC ORCID; Piris, Miguel A.; Vaqué, José P.
KeywordsBRAF
Targeted therapy
Melanoma
MAPK
Somatic mutations
Issue Date2015
PublisherImpact Journals
CitationOncotarget 6(28): 25452-25465 (2015)
AbstractTargeted treatment of advanced melanoma could benefit from the precise molecular characterization of melanoma samples. Using a melanoma-specific selection of 217 genes, we performed targeted deep sequencing of a series of biopsies, from advanced melanoma cases, with a Breslow index of =4 mm, and/or with a loco-regional infiltration in lymph nodes or presenting distant metastasis, as well of a collection of human cell lines. This approach detected 3-4 mutations per case, constituting unique mutational signatures associated with specific inhibitor sensitivity. Functionally, case-specific combinations of inhibitors that simultaneously targeted MAPK-dependent and MAPK-independent mechanisms were most effective at inhibiting melanoma growth, against each specific mutational background. These observations were challenged by characterizing a freshly resected biopsy from a metastatic lesion located in the skin and soft tissue and by testing its associated therapy ex vivo and in vivo using melanocytes and patient-derived xenografted mice, respectively. The results show that upon mutational characterization of advanced melanoma patients, specific mutational profiles can be used for selecting drugs that simultaneously target several deregulated genes/pathways involved in tumor generation or progression.
DescriptionThis is an open-access article distributed under the terms of the Creative Commons Attribution License.-- et al.
Publisher version (URL)http://dx.doi.org/10.18632/oncotarget.4545
URIhttp://hdl.handle.net/10261/130583
DOIhttp://dx.doi.org/10.18632/oncotarget.4545
Identifiersdoi: 10.18632/oncotarget.4545
e-issn: 1949-2553
Appears in Collections:(IBBTEC) Artículos
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