Secondary tumors arising in patients undergoing BRAF inhibitor therapy exhibit increased BRAF-CRAF heterodimerization

Lise Boussemart, Isabelle Girault, Hélène Malka-Mahieu, Christine Mateus, Emilie Routier, Margot Rubington, Nyam Kamsu-Kom, Marina Thomas, Gorana Tomasic, Sandrine Agoussi, Marie Breckler, Méllanie Laporte, Ludovic Lacroix, Alexander M. Eggermont, Andrea Cavalcanti, Florent Grange, Julien Adam, Stélphan Vagner, Caroline Robert

    Résultats de recherche: Contribution à un journalArticleRevue par des pairs

    36 Citations (Scopus)

    Résumé

    BRAF inhibitors (BRAFi) elicit therapeutic responses in metastatic melanoma, but alarmingly, also induce the formation of secondary benign and malignant skin tumors. Here, we report the emergence and molecular characterization of 73 skin and extracutaneous tumors in 31 patients who underwent BRAFi therapy. The majority of patients presented with classic epidermal tumors such as verrucous papillomas, keratoacanthomas, and squamous cell carcinomas (SCC). However, 15 patients exhibited new or rapidly progressing tumors distinct from these classic subtypes, such as lymph node metastasis, new melanomas, and genital and oral mucosal SCCs. Genotyping of the tumors revealed that oncogenic RAS mutations were found in 58% of the evaluable tumor samples (38/66) and 49% of the control tumors from patients not treated with BRAFi (30/62). Notably, proximity ligation assays demonstrated that BRAF- CRAF heterodimerization was increased in fixed tumor samples from BRAFi-treated patients compared with untreated patients. Our findings reveal that BRAF-CRAF complex formation is significantly associated with BRAFi treatment, and may therefore serve as a useful biomarker of BRAFi-induced cutaneous and extracutaneous tumor formation. Cancer Res; 76(6); 1476-84. 2016 AACR.

    langue originaleAnglais
    Pages (de - à)1476-1484
    Nombre de pages9
    journalCancer Research
    Volume76
    Numéro de publication6
    Les DOIs
    étatPublié - 15 mars 2016

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