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 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.
Cancer Genomics Group, IDIVAL, Instituto de Investigación Marqués de Valdecilla, Santander, Spain.
Soraya
S
Curiel-Olmo
Oncology Service, Hospital Universitario Marqués de Valdecilla, Santander, Spain.
Almudena
A
García-Castaño
Department of Pharmacology, University of Cantabria (UC), Santander, Spain, and Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), ISCIII, Madrid, Spain.|Instituto de Biomedicina y Biotecnología de Cantabria (IBBTEC), CSIC, Universidad de Cantabria, Departamento de Biología Molecular, Universidad de Cantabria, Santander, Spain.|Department of Pharmacology, Medicine School, Complutense University, Madrid, Spain.
Rebeca
R
Vidal
Cancer Genomics Group, IDIVAL, Instituto de Investigación Marqués de Valdecilla, Santander, Spain.
Helena
H
Pisonero
Instituto de Biomedicina y Biotecnología de Cantabria (IBBTEC), CSIC, Universidad de Cantabria, Departamento de Biología Molecular, Universidad de Cantabria, Santander, Spain.
Ignacio
I
Varela
Cancer Genomics Group, IDIVAL, Instituto de Investigación Marqués de Valdecilla, Santander, Spain.|Pathology Service, Hospital Universitario Marqués de Valdecilla, Santander, Spain.
Alicia
A
León-Castillo
Plastic Surgery Service Hospital Universitario Marqués de Valdecilla, Santander, Spain.
Eugenio
E
Trillo
Cancer Genomics Group, IDIVAL, Instituto de Investigación Marqués de Valdecilla, Santander, Spain.|Pathology Service, Hospital Universitario Marqués de Valdecilla, Santander, Spain.
Carmen
C
González-Vela
Cancer Genomics Group, IDIVAL, Instituto de Investigación Marqués de Valdecilla, Santander, Spain.
Nuria
N
García-Diaz
Cancer Genomics Group, IDIVAL, Instituto de Investigación Marqués de Valdecilla, Santander, Spain.
Carmen
C
Almaraz
Instituto de Biomedicina y Biotecnología de Cantabria (IBBTEC), CSIC, Universidad de Cantabria, Departamento de Biología Molecular, Universidad de Cantabria, Santander, Spain.
Thaidy
T
Moreno
Cancer Genomics Group, IDIVAL, Instituto de Investigación Marqués de Valdecilla, Santander, Spain.
Laura
L
Cereceda
Cancer Genomics Group, IDIVAL, Instituto de Investigación Marqués de Valdecilla, Santander, Spain.
Rebeca
R
Madureira
Cancer Genomics Group, IDIVAL, Instituto de Investigación Marqués de Valdecilla, Santander, Spain.
Nerea
N
Martinez
Dermatology Service, Instituto I+12, Hospital Universitario 12 de Octubre, Madrid, Spain.
Pablo
P
Ortiz-Romero
Department of Pharmacology, University of Cantabria (UC), Santander, Spain, and Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), ISCIII, Madrid, Spain.|Instituto de Biomedicina y Biotecnología de Cantabria (IBBTEC), CSIC, Universidad de Cantabria, Departamento de Biología Molecular, Universidad de Cantabria, Santander, Spain.
Elsa
E
Valdizán
Cancer Genomics Group, IDIVAL, Instituto de Investigación Marqués de Valdecilla, Santander, Spain.
Miguel A
MA
Piris
Cancer Genomics Group, IDIVAL, Instituto de Investigación Marqués de Valdecilla, Santander, Spain.
José P
JP
Vaqué
Cancer Genomics Group, IDIVAL, Instituto de Investigación Marqués de Valdecilla, Santander, Spain.|Pathology Service, Hospital Universitario Marqués de Valdecilla, Santander, Spain.
Miguel
M
Piris
Cancer Genomics Group, IDIVAL, Instituto de Investigación Marqués de Valdecilla, Santander, Spain.|Instituto de Biomedicina y Biotecnología de Cantabria (IBBTEC), CSIC, Universidad de Cantabria, Departamento de Biología Molecular, Universidad de Cantabria, Santander, Spain.
José
J
Vaqué
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000235:genetics*; D001706:Biopsy; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004252:DNA Mutational Analysis / Q000379:methods*; D020869:Gene Expression Profiling / Q000379:methods*; D020022:Genetic Predisposition to Disease; D006801:Humans; D008207:Lymphatic Metastasis; D008544:Melanocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics* / Q000556:secondary; D008807:Mice, Inbred BALB C; D016688:Mice, Inbred NOD; D008819:Mice, Nude; D058990:Molecular Targeted Therapy; D009154:Mutation; D018579:Patient Selection; D010641:Phenotype; D057285:Precision Medicine; D011237:Predictive Value of Tests; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D013997:Time Factors; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D047428:Protein Kinase Inhibitors
BRAF; MAPK; melanoma; somatic mutations; targeted therapy