Individualized strategies to target specific mechanisms of disease in malignant melanoma patients displaying unique mutational signatures
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AuthorCuriel del Olmo, Soraya; García Castaño, Almudena; Vidal Casado, Rebeca; Pisonero Fraga, Helena; Varela Egocheaga, Ignacio; León Castillo, Alicia; Trillo Bohajar, Eugenio; González Vela, María del Carmen; García Diaz, Nuria; Almaraz Pro, Carmen; Moreno Rodríguez, Thaidy; Cereceda Company, Laura; Madureira Rivero, Rebeca; Martínez Magunacelaya, Nerea; Ortiz Romero, Pablo; Valdizán Ruiz, Elsa María; Piris Pinilla, Miguel Ángel; Vaqué Díez, José Pedro
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.