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

Targeted 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...

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Autores principales: Curiel-Olmo, Soraya, García-Castaño, Almudena, Vidal, Rebeca, Pisonero, Helena, Varela, Ignacio, León-Castillo, Alicia, Trillo, Eugenio, González-Vela, Carmen, García-Diaz, Nuria, Almaraz, Carmen, Moreno, Thaidy, Cereceda, Laura, Madureira, Rebeca, Martinez, Nerea, Ortiz-Romero, Pablo, Valdizán, Elsa, Piris, Miguel, Vaqué, José
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4694844/
https://www.ncbi.nlm.nih.gov/pubmed/26327537
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author Curiel-Olmo, Soraya
García-Castaño, Almudena
Vidal, Rebeca
Pisonero, Helena
Varela, Ignacio
León-Castillo, Alicia
Trillo, Eugenio
González-Vela, Carmen
García-Diaz, Nuria
Almaraz, Carmen
Moreno, Thaidy
Cereceda, Laura
Madureira, Rebeca
Martinez, Nerea
Ortiz-Romero, Pablo
Valdizán, Elsa
Piris, Miguel
Vaqué, José
author_facet Curiel-Olmo, Soraya
García-Castaño, Almudena
Vidal, Rebeca
Pisonero, Helena
Varela, Ignacio
León-Castillo, Alicia
Trillo, Eugenio
González-Vela, Carmen
García-Diaz, Nuria
Almaraz, Carmen
Moreno, Thaidy
Cereceda, Laura
Madureira, Rebeca
Martinez, Nerea
Ortiz-Romero, Pablo
Valdizán, Elsa
Piris, Miguel
Vaqué, José
author_sort Curiel-Olmo, Soraya
collection PubMed
description Targeted 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.
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spelling pubmed-46948442016-01-20 Individualized strategies to target specific mechanisms of disease in malignant melanoma patients displaying unique mutational signatures Curiel-Olmo, Soraya García-Castaño, Almudena Vidal, Rebeca Pisonero, Helena Varela, Ignacio León-Castillo, Alicia Trillo, Eugenio González-Vela, Carmen García-Diaz, Nuria Almaraz, Carmen Moreno, Thaidy Cereceda, Laura Madureira, Rebeca Martinez, Nerea Ortiz-Romero, Pablo Valdizán, Elsa Piris, Miguel Vaqué, José Oncotarget Research Paper Targeted 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. Impact Journals LLC 2015-07-25 /pmc/articles/PMC4694844/ /pubmed/26327537 Text en Copyright: © 2015 Curiel-Olmo et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Paper
Curiel-Olmo, Soraya
García-Castaño, Almudena
Vidal, Rebeca
Pisonero, Helena
Varela, Ignacio
León-Castillo, Alicia
Trillo, Eugenio
González-Vela, Carmen
García-Diaz, Nuria
Almaraz, Carmen
Moreno, Thaidy
Cereceda, Laura
Madureira, Rebeca
Martinez, Nerea
Ortiz-Romero, Pablo
Valdizán, Elsa
Piris, Miguel
Vaqué, José
Individualized strategies to target specific mechanisms of disease in malignant melanoma patients displaying unique mutational signatures
title Individualized strategies to target specific mechanisms of disease in malignant melanoma patients displaying unique mutational signatures
title_full Individualized strategies to target specific mechanisms of disease in malignant melanoma patients displaying unique mutational signatures
title_fullStr Individualized strategies to target specific mechanisms of disease in malignant melanoma patients displaying unique mutational signatures
title_full_unstemmed Individualized strategies to target specific mechanisms of disease in malignant melanoma patients displaying unique mutational signatures
title_short Individualized strategies to target specific mechanisms of disease in malignant melanoma patients displaying unique mutational signatures
title_sort individualized strategies to target specific mechanisms of disease in malignant melanoma patients displaying unique mutational signatures
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4694844/
https://www.ncbi.nlm.nih.gov/pubmed/26327537
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