Oncotarget

Research Papers:

This article has been corrected. Correction in: Oncotarget. 2016; 7(5):6352.

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

Soraya Curiel-Olmo, Almudena García-Castaño, Rebeca Vidal, Helena Pisonero, Ignacio Varela, Alicia León-Castillo, Eugenio Trillo, Carmen González-Vela, Nuria García-Diaz, Carmen Almaraz, Thaidy Moreno, Laura Cereceda, Rebeca Madureira, Nerea Martinez, Pablo Ortiz-Romero, Elsa Valdizán, Miguel Angel Piris and José Pedro Vaqué _

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Oncotarget. 2015; 6:25452-25465. https://doi.org/10.18632/oncotarget.4545

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Abstract

Soraya Curiel-Olmo1,*, Almudena García-Castaño2,*, Rebeca Vidal3,4,8, Helena Pisonero1, Ignacio Varela4, Alicia León-Castillo1,5, Eugenio Trillo6, Carmen González-Vela1,5, Nuria García-Diaz1, Carmen Almaraz1, Thaidy Moreno4, Laura Cereceda1, Rebeca Madureira1, Nerea Martinez1, Pablo Ortiz-Romero7, Elsa Valdizán3,4, Miguel Angel Piris1,5,#, José Pedro Vaqué1,4,#

1Cancer Genomics Group, IDIVAL, Instituto de Investigación Marqués de Valdecilla, Santander, Spain

2Oncology Service, Hospital Universitario Marqués de Valdecilla, Santander, Spain

3Department of Pharmacology, University of Cantabria (UC), Santander, Spain, and Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), ISCIII, Madrid, Spain

4Instituto de Biomedicina y Biotecnología de Cantabria (IBBTEC), CSIC, Universidad de Cantabria, Departamento de Biología Molecular, Universidad de Cantabria, Santander, Spain

5Pathology Service, Hospital Universitario Marqués de Valdecilla, Santander, Spain

6Plastic Surgery Service Hospital Universitario Marqués de Valdecilla, Santander, Spain

7Dermatology Service, Instituto I+12, Hospital Universitario 12 de Octubre, Madrid, Spain

8Department of Pharmacology, Medicine School, Complutense University, Madrid, Spain

*These authors have contributed equally to this work

#Senior author

Correspondence to:

José Pedro Vaqué, e-mail: [email protected]

Keywords: Targeted therapy, melanoma, BRAF, MAPK, somatic mutations

Received: March 25, 2015     Accepted: July 13, 2015     Published: July 25, 2015

ABSTRACT

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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